Migdalska-Richards Et Al-2016-Journal of Neurochemistry

JOURNAL OF NEUROCHEMISTRY | 2016 | 139 (Suppl. 1) | 77–90 doi: 10.1111/jnc.
13385
Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK
Abstract PD-GBA1 is identical to idiopathic PD, with nigral dopamine

Parkinson disease (PD) is the second most common neu- cell loss, Lewy bodies, and neurites containing alpha-
rodegenerative disorder after Alzheimer disease, whereas synuclein. The mechanism by which GBA1 mutations increase
Gaucher disease (GD) is the most frequent lysosomal storage the risk for PD is still unknown. However, given that clinical
disorder caused by homozygous mutations in the glucocere- manifestation and pathological findings in PD-GBA1 patients
brosidase (GBA1) gene. Increased risk of developing PD has are almost identical to those in idiopathic PD individuals, it is
been observed in both GD patients and carriers. It has been likely that, as in idiopathic PD, alpha-synuclein accumulation,
estimated that GBA1 mutations confer a 20- to 30-fold mitochondrial dysfunction, autophagic impairment, oxidative
increased risk for the development of PD, and that at least and endoplasmic reticulum stress may contribute to the
7–10% of PD patients have a GBA1 mutation. To date, development and progression of PD-GBA1. Here, we review
mutations in the GBA1 gene constitute numerically the most the GBA1 gene, its role in GD, and its link with PD.
important risk factor for PD. The type of PD associated with Keywords: alpha-synuclein, Gaucher disease,
GBA1 mutations (PD-GBA1) is almost identical to idiopathic glucocerebrosidase 1 (GBA1), lysosome, mitochondria,
PD, except for a slightly younger age of onset and a tendency Parkinson disease.
to more cognitive impairment. Importantly, the pathology of J. Neurochem. (2016) 139 (Suppl. 1), 77–90.
This article is part of a special issue on Parkinson disease.
Glucocerebrosidase 1 gene Northern blot analysis revealed the existence of at least

two GBA1 mRNAs (2.2 and 2.6 kb in length) that arise as a
The human glucocerebrosidase 1 (GBA1) gene maps to the result of alternate polyadenylation sites (Horowitz et al.
1q21 region and consists of 11 exons within a 7.6 kb
sequence (Horowitz et al. 1989; Cormand et al. 1997).
Received May 26, 2015; revised manuscript received September 8,
Approximately, 16 kb downstream of GBA1 lies an almost
2015; accepted October 2, 2015.
identical sequence consisting of 11 exons within a 5.7 kb Address correspondence and reprint requests to Prof. Anthony
sequence (Horowitz et al. 1989; Sorge et al. 1990). Despite Schapira MD, DSc, FRCP, FMedSci, Head of Department of Clinical
large deletions of Arthrobacter luteus sequences flanked by Neurosciences, UCL Institute of Neurology, London NW3 2PF, UK.
direct repeats in the introns, this pseudogene shares 96% E-mail: [email protected]
Abbreviations used: Alu, Arthrobacter luteus; ATG, methionine; BiP,
coding sequence similarity with the functional gene (Horow-
binding immunoglobulin protein; CBE, condruitol b-epoxide; CHOP,
itz et al. 1989). As some mutations found in the functional C/EBP homologous protein; CLEAR, coordinated lysosomal expression
gene can naturally occur within the pseudogene, the presence and regulation; CMA, chaperone-mediated autophagy; CNS, central
of the highly homologous pseudogene in close proximity to nervous system; DJ-1, Parkinson protein 7; ER, endoplasmic reticulum;
the functional gene complicates molecular identification of ERAD, ER-associated degradation; FDA, Food and Drug Administra-
tion; GD, Gaucher disease; GBA1, glucocerebrosidase; GCase, gluco-
known and novel GBA1 mutations. Therefore, a method
cerebrosidase enzyme; LIMP2, lysosomal membrane protein 2; LRRK2,
allowing the GBA1 gene to be distinguished from the leucine-rich repeat kinase 2; MPR, mannose-6-phosphate receptor;
pseudogene is crucial for reliable molecular diagnosis. One mRNA, messenger RNA; PARK2, parkin RBR E3 ubiquitin protein
such method utilizes a long-template polymerase chain ligase; PCR, polymerase chain reaction; PC12, pheochromocytoma; PD,
reaction (PCR) where genomic fragments of differing lengths Parkinson disease; PD-GBA1, Parkinson-GBA1; pH, power of hydrogen;
PINK1, PTEN-induced putative kinase 1; PI4K, phosphatidylinositol
from both the gene and the pseudogene are amplified
4-kinase; PTEN, phosphatase and tensin homolog; SNCA, alpha-
simultaneously, before being purified and subsequently used synuclein; TFEB, transcription factor EB; UPR, unfolded protein
for mutation identification (Tayebi et al. 1996). response.
© 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of 77
International Society for Neurochemistry, J. Neurochem. (2016) 139 (Suppl. 1), 77--90
This is an open access article under the terms of the Creative Commons Attribution License, which permits use,
distribution and reproduction in any medium, provided the original work is properly cited.
78 A. Migdalska-Richards and A. H. V. Schapira
1989).The GBA1 mRNA has two in-frame methionine start enlarged spleen containing unusual looking cells (Gaucher
codons located in exons 1 and 2, and both methionines are 1882). GD is the most common autosomal recessive
translated to produce functional protein in vitro (Sorge et al. lysosomal storage disorder. Its most characteristic hallmark
1985, 1987a). The protein using the start codon in exon 1 is the presence of glucocerebroside-laden macrophages in the
contains a 39-amino acid signal peptide, while the protein liver, spleen, and bone marrow, known as Gaucher cells. The
arising from the start codon in exon 2 contains only a 19- most common clinical features of GD include hep-
amino acid signal peptide. Both are processed to a 496-amino atosplenomegaly, thrombocytopenia, anemia, bone involve-
acid long mature protein after their signal peptide sequences ment with osteopenia, osteoporosis, and bone pain because
are removed, which is a common occurrence for secreted of bone infarcts or pathological fractures (Beutler and
proteins like glucocerebrosidase (Sorge et al. 1987b). Grabowski 2001). GD has been traditionally divided into
GBA1 encodes glucocerebrosidase (GCase), a lysosomal three distinct clinical forms based on age of onset and
enzyme that catalyses the hydrolysis of glycolipid gluco- involvement of the central nervous system (CNS) (Cox and
cerebroside to ceramide and glucose (Beutler 1992). Gluco- Schofield 1997). Type 1 GD (OMIM, #230800) is by far the
cerebrosidase is ubiquitously expressed in all types of tissues most common form and is classified as non-neuronopathic
(The Human Protein Atlas). As with other lysosomal since it does not affect the CNS. The disease course of type 1
proteins, GCase is synthetized in the rough endoplasmic GD is very heterogeneous with some patients developing first
reticulum (ER). However, in contrast to the majority of other symptoms in early childhood and others not manifesting any
lysosomal proteins, transport of GCase from the ER to symptoms until well into adulthood. Type 2 and type 3 GD
lysosomes is not mediated by mannose-6-phosphate recep- are classified as neuronopathic forms. Type 2 GD (OMIM,
tors, but via lysosomal membrane protein 2 (LIMP2). GCase #230900) is the acute neuronopathic form with onset in
binds to a coiled-coil domain in the lumenal region of LIMP2 infancy. It is characterized by rapid progression of neuro-
at neutral pH of the ER, and both proteins persist together logical symptoms leading to death within 2 years of age.
through the Golgi apparatus and endosomes into the Infants are apparently normal for the first few months of life,
lysosome, where acidic pH facilitates their dissociation after which they display hepatosplenomegaly, developmental
(Reczek et al. 2007). Sequential traversing of GCase and the regression, growth arrest, and rapid neurological decline
LIMP2 complex is dependent on two phosphatidylinositol 4- (Stone et al. 2000). Type 3 GD (OMIM, #231000) is a
kinases (PI4Ks), with the catalytic activity of the PI4K type chronic neuronopathic form with onset in early childhood.
IIIb (PI4KIIIb) kinase required for exit of the complex from Unlike type 2, it is characterized by slow progression of
the Golgi apparatus, and the PI4K type IIa (PI4KIIa) kinase neurological symptoms with parallel manifestation of all
needed for correct sorting of the complex from endosomes to clinical symptoms diagnosed in type 1 GD leading to death
lysosomes (Jovic et al. 2012). in early adulthood (Beutler and Grabowski 2001). The
The crystal structure of GCase, first obtained in 2003, prevalence of GD in the general population is about
revealed that GCase has three non-continuous domains. 1/40 000–1/50 000 live births, while the incidence of GD
Domain I consists of a three-stranded anti-parallel b-sheet. It among Jews of Ashkenazi origin is up to 1/450 live births
contains two disulphide bridges, which may be involved in with a carrier frequency of about 6% (Grabowski 2008;
GCase folding. Domain II consists of two b-sheets that form National Organization of Rare Disorders 2013; Bronstein
an immunoglobulin-like domain. Finally, domain III consists et al. 2014).
of an eight-stranded b/a triose phosphate isomerase (TIM) GD is caused by mutations in the GBA1 gene that lead to
barrel and contains the catalytic site of GCase (Dvir et al. deficiency of the lysosomal enzyme glucocerebrosidase
2003). (GCase). Nearly, 300 pathogenic changes in GBA1, includ-
The human GCase is glycosylated at four out of five ing point mutations, splice-site mutations, deletions, inser-
available asparagine residues (N19, N59, N146, and N270, tions, and recombinant alleles containing genomic sequences
but not N462), and glycosylation is required for its catalytic of both the gene and pseudogene, have been identified
function. It has been shown that mutations of asparagine (Hruska et al. 2008). These alterations lead to production of
residues N59, N146, and N270 do not affect GCase catalytic misfolded mutant enzymes with significantly reduced activ-
function and GCase interaction with active site-directed ity. GCase activity in GD patients is typically only 10–20%
inhibitors and activators. However, mutations of asparagine of that in normal individuals, while GCase activity in carriers
residue N19 result in production of catalytically inactive is about 50%. It is thought that, not only GCase deficiency,
enzyme (Berg-Fussman et al. 1993). but also ER stress triggered by the presence of misfolded
GCase contribute to the pathogenesis of GD. The two most
common GBA1 mutations identified in GD patients are
Gaucher disease
N370S and L444P (Sidransky and Lopez 2012). Interest-
Gaucher disease (GD) is named after Dr Philippe Gaucher ingly, the type of mutation is broadly predictive of GD form,
who, in 1882, first described a young woman with an as patients homozygous or compound heterozygous for the
© 2016 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of
The relationship between GBA1 mutations and PD 79
N370S mutation exclusively develop type 1 GD, patients non-inhibitory small molecular chaperones, was discovered.
homozygous for the L444P mutation are most likely to The pyrazolopyrimidines act as GCase activators that lead to
develop type 3 GD, while patients identified with a complex both an increase in GCase translocation to the lysosomes and
allele and a heterozygous L444P mutation are most likely to in GCase activity in wild-type and mutant (N370S/N370S
develop type 2 GD (Grabowski 2008; Sidransky 2012). The and L444P/L444P) human fibroblasts (Patnaik et al. 2012).
severity of the GD phenotype in relation to the observed Another promising small molecular chaperone, ambroxol
mutation might be explained by the effect, which the hydrochloride (from now on commonly referred to as
particular mutation has on the GCase structure. Namely, ambroxol), was identified after screening the library of Food
the N370S mutation, which is situated on the longest a-helix and Drug Administration-approved drugs with a thermal
of GCase at the interface of domain II and III, does not denaturation assay using wild-type GCase (Maegawa et al.
directly affect the catalytic activity of GCase since it located 2009). Ambroxol has long been used to treat airway mucus
too far from the catalytic site of domain III. The L444P hypersecretion and hyaline membrane disease in newborns,
mutation, which is situated at the hydrophobic core of which demonstrates its non-toxicity to humans. Ambroxol
domain II, causes conformational changes to the core and to acts as a GCase mixed-type inhibitor with its inhibitory
domain II, which might result in the generation of unstable property toward GCase being highest at the neutral pH of the
GCase (Dvir et al. 2003). endoplasmic reticulum and void at the acidic pH of the
Currently, two types of treatment are available for patients lysosomes where functional GCase is required (Maegawa
with GD: enzyme replacement therapy (using imiglucerase, et al. 2009). Several studies have demonstrated that
velaglucerase alfa, or taliglucerase alfa) and substrate ambroxol treatment of different lines of cultured human
reduction therapy (using misglustat) (Bennett and Mohan GD fibroblasts results in a significant increase in GCase
2013). Although these treatments greatly improve the activity (Maegawa et al. 2009; Bendikov-Bar et al. 2011,
peripheral (non-neuronopathic) features of the disease, they 2013; Luan et al. 2013; McNeill et al. 2014). However,
are ineffective for treatment of neuronopathic symptoms of whether an increase in GCase activity is because of
type 2 and type 3 GD as they do not cross the blood–brain ambroxol’s chaperone activity alone remains to be clarified,
barrier (Bennett and Mohan 2013). Emerging treatments in as it has been shown in a fibroblast model that ambroxol
the form of small molecular chaperones designed to cross the increased GCase activity by activating the coordinated
blood–brain barrier, which are able to bind misfolded mutant lysosomal expression and regulation network (coordinated
GCase in the endoplasmic reticulum, help its correct folding lysosomal expression and regulation) via the action of
and subsequently assist its transport to the lysosomes, give transcription factor EB, which in turn led to an increase in
great promise for treatment of the neuronopathic features of lysosomal biogenesis. An enhancement of lysosomal mass
GD. The ability of small molecular chaperones to bind to would most likely lead to an increase in GCase activity, not
misfolded GCase (and subsequently to induce proper folding necessarily via the elevated chaperone activity of ambroxol
of mutant GCase that in turn would increase functional (McNeill et al. 2014). Currently available data from
GCase levels in the lysosomes) is particularly important, as it ambroxol-treated wild-type and transgenic mice carrying
has been shown that majority of GBA1 mutations lead to the human GBA1 mutations has convincingly shown increase in
production of misfolded GCase (Sawkar et al. 2002; Bernier GCase activity in the peripheral organs, but variable change
et al. 2004; Suzuki et al. 2009; Patnaik et al. 2012). Several in the brain. Hence, more studies are required to determine
such small molecular chaperones that lead to an increase in the effect of ambroxol on GCase activity in the CNS (Luan
GCase activity have been investigated in both cell and animal et al. 2013; Sanders et al. 2013).
models (Sawkar et al. 2002; Bernier et al. 2004; Steet et al.
2006; Maegawa et al. 2009; Bendikov-Bar et al. 2011;
The link between GBA1 and Parkinson disease
Patnaik et al. 2012; Bendikov-Bar et al. 2013; Luan et al.
2013). GCase inhibitors (e.g. N-(n-nonyl)deoxynojirimycin, The link between GD and Parkinson disease (PD) was
and isofagomine) were the first chaperones shown to increase initially regarded as incidental, thus the first publications
GCase activity. Both N-(n-nonyl)deoxynojirimycin and describing Gaucher patients with Parkinsonian features
isofagomine increased GCase activity by increasing GCase originated from individual clinics (McKeran et al. 1985;
trafficking to the lysosomes through specific, but reversible Turpin et al. 1988; Tayebi et al. 2001). The increasing
binding of GCase in the ER. Although they led to an increase number of reports suggesting the association between
in GCase activity in fibroblasts derived from Gaucher mutations in the GBA1 gene and PD led to more compre-
patients, it has been demonstrated that their clinical appli- hensive studies focusing on several Gaucher patients with PD
cation is compromised because of difficulties in balancing (Bembi et al. 2003; Tayebi et al. 2003; Varkonyi et al.
chaperone activity with the direct inhibition of GCase 2003). Moreover, an increased proportion of PD cases in GD
activity (Sawkar et al. 2002; Bernier et al. 2004; Steet et al. carriers compared to the general population further indicated
2005). Subsequently, a class of pyrazolopyrimidines, the first the association of the GBA1 gene with PD (Goker-Alpan
et al. 2004; Halperin et al. 2006). This finding led patients have a GBA1 mutation (Sidransky et al. 2009;
researchers to investigate whether the frequency of GBA1 Bultron et al. 2010; McNeill et al. 2012a,b). However, not
mutations is increased in PD. The first such study identified all GBA1 mutant carriers will develop PD, and it is currently
GBA1 mutations in 12 of 57 (21%) PD postmortem brains estimated that 30% will develop the disease by age 80 years
(Lwin et al. 2004). This study not only further supported the (Lesage and Brice 2009; Lesage et al. 2011).
link between GBA1 and PD, but also indicated that both
heterozygous and homozygous mutations in GBA1 might be
GBA1-associated PD (PD-GBA1) – clinical and
associated with PD. Subsequently, multiple PD patients were
biochemical presentation
investigated to establish the prevalence of GBA1 mutations,
which highlighted the importance of routine GBA1 mutation Individual PD patients with GBA1 mutations cannot be
screening when diagnosing PD individuals. The approach distinguished at the clinical level from idiopathic PD patients
taken by different research groups varied, as some screened without GBA1 mutations. Parkinson-GBA1 (PD-GBA1)
only for the most common GBA1 mutations, while others patients exhibit the classic triad of bradykinesia, rigidity,
sequenced all exons of the gene (Tables 1–3). Overall, data and tremor, with asymmetric onset (Goker-Alpan et al.
acquired from multiple studies showed that the frequency of 2008). However, age of onset tends to be slightly younger, an
heterozygous GBA1 mutations varied between 2.3–9.8% in incidence of neuropsychiatric features (such as depression,
the European population of non-Ashkenazi Jewish origin, anxiety, hallucination, and sleep disturbance) is higher, and
16.9–31.3% in the European population of Ashkenazi Jewish there is a greater risk for earlier and more prevalent cognitive
origin, 1.8–8.7% in the Asian population, and 2.9–8.0% in impairment in PD-GBA1 patients (Tan et al. 2007; Neumann
the combined North–South American population (Tables et al. 2009; Sidransky et al. 2009; Brockmann et al. 2011;
1–3). The most common mutations identified in the European McNeill et al. 2012b; Winder-Rhodes et al. 2013). The
population of non-Ashkenazi Jewish origin were L444P and pattern of cognitive dysfunction in GBA1-positive carriers is
N370S, and both mutations were found with similar subtly different, present in those even without PD at the time
frequency (Table 1). Interestingly, in the European popula- of investigation (Zokaei et al. 2014). Nigrostriatal imaging
tion of Ashkenazi Jewish origin, the N370S mutation was the with fluorodopa positron emission tomography or single
most predominant, while in the Asian and North–South photon emission tomography with dopamine sensitive
American populations, the L444P mutation was the most ligands in PD-GBA1 demonstrate an asymmetric pattern of
prevalent (Tables 1–3). Moreover, most studies conducted abnormality indistinguishable from idiopathic PD (Goker-
on European PD individuals of Ashkenazi Jewish origin did Alpan et al. 2012; McNeill et al. 2013b). This contrasts with
not detect any L444P mutations, while the majority of studies the imaging of parkin (parkin RBR E3 ubiquitin protein
carried out on PD patients from the Asian population did not ligase, PARK2) or phosphatase and tensin homolog-induced
identify any N370S mutations (Tables 1 and 2). Neverthe- putative kinase 1 (PINK1) mutant PD, where abnormalities
less, given the observed discrepancies in incidence of GBA1 are usually symmetrical. Patients with GBA1 mutations also
mutations within the same population, and the limited exhibit retinal thinning as determined by optical coherence
number of cases and controls available for individual studies, tomography compared to matched controls and similar to that
a much bigger study was required to provide a conclusive seen in PD patients (McNeill et al. 2013a).
answer about the frequency of GBA1 mutations among Current evidence suggests that GBA1 mutant homozygote
people of different origin. A multicenter meta-analysis and heterozygote carriers without clinical evidence of PD,
collected a total of 5691 PD patients and 4898 controls exhibit the prodromal features of the disease. Olfactory
(Sidransky et al. 2009). They analyzed 780 PD individuals function and cognitive assessment were significantly
and 387 controls of Ashkenazi Jewish origin for both the reduced, and motor testing abnormal in GBA1-positive cases
N370S and L444P mutations, and found that 15% of patients without features of PD compared to controls (McNeill et al.
and 3% of controls had one of the two mutations. They also 2012b). A 2 year follow-up showed significant deterioration
screened 4911 PD individuals and 4511 controls of non- in scores for depression, rapid eye movement sleep behavior
Ashkenazi Jewish origin and found that 3% of patients and disorder, cognition, olfaction, and motor scores (Beavan
less than 1% of controls had at least one of the two et al. 2015). The GBA1 cohort exhibits a relatively rapid
mutations. Finally, they sequenced the entire GBA1 gene in evolution of non-motor and motor features.
1883 PD individuals of non-Ashkenazi Jewish origin and The response to dopaminergic therapy in PD-GBA1
found that 7% of patients carried GBA1 mutations. To appears to be the same as that seen in idiopathic PD (Ziegler
summarize, mutations in the GBA1 gene constitute numer- et al. 2007)., including the development of motor complica-
ically the most important predisposing risk factor for tions. In one center, retrospective genetic analysis identified
developing PD. Both homozygous and heterozygous GBA1 GBA1 mutations in 17% of those who had undergone deep-
confer a 20- to 30-fold increased risk for the development of brain stimulation, and in whom clinical effect was as good as
PD, and it is estimated that approximately 5–10% of PD those without mutations (Angeli et al. 2013).
Table 1 Frequency and type of GBA1 mutations found in the European population.
Number % with mutation
PD Control PD Control Most common

cases cases cases cases Method Alterations found mutation(s) Origin Reference
2350 1111 4.5 0.63 Screening of GBA1 exon 9 and 10 N370S, L444P, D443N, and – Italian Asselta et al. 2014
IVS10+1G>T
259 – 3.5 – Sequencing of GBA1 exons L444P, N370S, N462K, R463C, and N370S (33.33%) British Winder-Rhodes et al. 2013
R257Q L444P (33.33%)
360 348 5.8 1.4 Sequencing of GBA1 exon 8 to 11 N370S, D409H, H255Q, L444P, N370S (33.33%) Serbian Kumar et al. 2013
A456P, R463C, and RecNciI
311 474 2.3 1.7 Genotyping for L444P and N370S L444P and N370S N370S (57.14%) Norwegian Toft et al. 2006
L444P (42.86%)
225 186 9.8 0.5 Sequencing of GBA1 exons M123T, L144V, G202R, I260T, L444P (27.27%) Spanish Seto
-Salvia et al. 2012
T369M, N370S, W393R, D409H, N370S (22.72%)
L444P, RecNciI, and S488T
330 240 2.7 0.4 Genotyping for L444P and N370S L444P and N370S L444P (66.67%) Russian Emelyanov et al. 2012
1391 391 6.7 1.0 Sequencing of GBA1 exons Lots of different mutations N370S (47.40%) French Lesage et al. 2011
205 206 10.24 3.39 Genotyping for N370S, D409H, N370S, L444P, D409H; H255Q, N370S (28.57%) Greek Moraitou et al. 2011
L444P, H255Q, R120W, D409H, Y108C, IVS10-1G>A L444P (28.57%)
Y108C, IVS6-2A>G, and
IVS10-1G>A
230 430 6.1 0.7 Sequencing of GBA1 exons N370S, N396T, D409H, and L444P N370S (33.33%) Portuguese Bras et al. 2009
N396T (33.33%)
172 132 3.4 0.3 Sequencing of GBA1 exons L445P, D409H, E326K, H255Q, H255Q (36.36%) Greek Kalinderi et al. 2009
R329H, L268L, S271G, T428K, and L444P (18.18%)
V460L
790 257 4.18 1.17 Sequencing of GBA1 exons L444P, D443N, R463C, RecNciI, L444P (33.33%) British Neumann et al. 2009
RecA456P, N370S, D409H, N370S (24.24%)
D380A, c.1263-1317del55, R257Q,
G193E, R131C, K7E, and V458L
420 4138 17.9 4.2 Genotyping for N370S, R496H, N370S, R496H, 84GG, IVS2+1, N370S (61.33%) Ashkenazi Gan-Or et al. 2008
84GG, IVS2+1, V394L, D409H, V394L, L444P, and RecTL Jewish (Israeli)
L444P, and RecTL
395 483 2.8 0.2 Genotyping for L444P and N370S L444P and N370S L444P (72.73%) Italian De Marco et al. 2008
178 85 16.9 7.1 Sequencing of GBA1 exons N370S, R496H, E326K, T369M, N370S (78.33%) Ashkenazi Jewish Clark et al. 2007
P175P, and 84insGG (American)
99 1543 31.3 6.2 Genotyping for N370S, L444P, N370S and 84GG N370S (83.87%) Ashkenazi Aharon-Peretz et al. 2004
84GG, IVS2+1G>A, V394L, Jewish (Israeli)
and R496H
The relationship between GBA1 mutations and PD
81
82
Table 2 Frequency and type of GBA1 mutations found in the Asian population.
Number % with mutation

Most common
PD cases Control cases PD cases Control cases Method Alterations found mutation(s) Origin Reference
184 130 8.7 5.4 Sequencing of GBA1 exons c.334_338delCAGAA L444P (31.25%) Chinese Yu et al. 2015
L264I, L314V, R163Q, F213I,
E326K, S364S, F347L, V375L,
L444P, RecNciI, and Q497R
A. Migdalska-Richards and A. H. V. Schapira
480 395 5 0.5 Sequencing of GBA1 exons L444P, N386K, P428S, IVS2þ1G>A, L444P (58%) Thai Pulkes et al. 2014
IVS9þ3G>C, IVS10-9_10GT>AG,
and c.1309delG
195 443 3.08 0.0 Genotyping for L444P, N370S, and L444P L444P (100%) Chinese Zhang et al. 2012
R120W mutations
277 291 3.2 0.0 Sequencing of GBA1 exons N188S, P201H, R257Q, S271G, and R257Q (33.33%) Korean Choi et al. 2012
L444P L444P (22.22%)
208 298 3.4 0.3 Genotyping for L444P, N370S, and L444P L444P (100%) Chinese Wang et al. 2012
R120W mutations
967 780 3.72 0.26 Sequencing of GBA1 exons (30 L444P, RecNciI, and D409H L444P (75%) Chinese Huang et al. 2011
cases) Genotyping for L444P,
D409H, R120W, L174P, and
Q497R mutations (all individuals)
328 300 1.8 0.7 Genotyping for N370S mutation N370S N370S (100%) Chinese Hu et al. 2010
616 411 3.2 0.2 Genotyping for L444P mutation L444P L444P (100%) Chinese Mao et al. 2010
402 412 2.74 0.0 Genotyping for L444P, N370S, L444P L444P (100%) Chinese Sun et al. 2010a,b
F213I, and R353W mutations
331 347 8 0.0 Genotyping for L444P and N370S L444P L444P (100%) Chinese Tan et al. 2007
mutations
518 339 3.1 1.2 Genotyping for L444P, RecNciI, and L444P, RecNciI and R120W L444P (81.25%) Taiwanese Wu et al. 2007
R120W mutations
92 92 4.1 1.1 Sequencing of GBA1 exons L444P, D409H, L174P, and Q497R Each mutation (25%) Taiwanese Ziegler et al. 2007
n
Importantly, the pathology of PD-GBA1 is identical to that
lez-Del Rinco
of idiopathic PD with nigral dopamine loss and Lewy bodies
Mde et al. 2013
Clark et al. 2007

Spitz et al. 2008
Mata et al. 2008
Sato et al. 2005

and neurites containing alpha-synuclein (Westbroek et al.
Reference
2011; Swan and Saunders-Pullman 2013).
Gonza
Pathogenesis of PD-GBA1
Canadian
American The mechanism by which GBA1 mutations increase the risk
American
Brazilian
Mexican
Origin
of PD is still unknown. However, given that clinical

manifestation and pathological findings are almost identical
in PD-GBA1 and idiopathic PD patients, it is thought that, as
L444P (47.62%)
N370S (52.38%)
in idiopathic PD, alpha-synuclein accumulation, mitochon-

T369M (25%)
RecNciI (60%)
L444P (100%)
L444P (100%)
Most common
L444P (25%)
drial impairment, autophagic dysfunction, inflammation, and

mutation(s)
oxidative and endoplasmic reticulum stress may play an

important role in both the development and progression of
PD-GBA1 (Schapira and Tolosa 2010).
In contrast to autosomal recessive forms of PD (caused by
D409H, and RecNciI
homozygous mutations in PARK2, PINK1, or DJ-1) and

L444P and N370S
Table 3 Frequency and type of glucocerebrosidase (GBA1) mutations found in the combined North–South American population.
Alterations found
autosomal dominant forms of PD (caused by heterozygous

N370S, T369M,
L444P, N370S,
and RecNciI
mutations in alpha-synuclein (SNCA) or leucine-rich repeat

kinase 2), PD-GBA1 supports both autosomal recessive and
L444P
L444P
autosomal dominant modes of inheritance (Sidransky 2012).

Autosomal recessive inheritance is generally associated
with loss-of-function of mutated proteins, and several
Genotyping for L444P and N370S mutations
Genotyping for L444P and N370S mutations
characteristics of GBA1 suggest loss-of-function of mutated

Genotyping for N370S, L444P and G377S
GCase.
K198T, R329C, 84insGG, and RecNciI
Genotyping for N370S, L444P, IVS2≦1
• A subset of PD-GBA1 patients is identified with null

GBA1 alleles, such as 84GG and IVS2+1G>A, which do
not encode GCase (Aharon-Peretz et al. 2004; Gan-Or
Sequencing of GBA1 exons
et al. 2008; Clark et al. 2009).

• Inhibition of GBA1 with condruitol b-epoxide (CBE) in
cell and animal models leads to alpha-synuclein accumu-
lation (Manning-Bo g et al. 2009; Cleeter et al. 2013).
• Homozygous knock-out of the Gba1 gene in mice leads
Method
to mitochondrial dysfunction, and lipid and alpha-

synuclein accumulation (Enquist et al. 2007; Osellame
et al. 2013).
Control cases
Autosomal dominant inheritance is often associated with

gain-of-function of mutated proteins, and several features of
GBA1 suggest gain-of-function of mutated GCase.
0.98
•
0.0
0.0
0.4
2.1
% with mutation
Most PD-GBA1 patients are identified with heterozygous

GBA1 mutations.
•
PD cases
The missense mutations resulting in production of

misfolded GCase account for the majority of GBA1
5.47
3.08
5.68
2.9
mutations.
• Misfolded GCase interacts directly with alpha-synuclein,
Control cases
which subsequently leads to increased alpha-synuclein

accumulation (Sidransky and Lopez 2012).
252
267
554
102
Even though there is evidence supporting loss- and gain-

94
of-function of GCase, both hypotheses have limitations, as

PD cases
presence of null mutations in some PD-GBA1 patients

Number
contradicts the gain-of-function theory, while development

128
721
100
65
88
of PD-GBA1 in individuals carrying heterozygous GBA1
mutations contradicts the loss-of-function theory. Further- oligomer formation (Mazzulli et al. 2011; Westbroek et al.
more, misfolded GCase and loss-of-function may result in a 2011; Sidransky and Lopez 2012). Further evidence sup-
secondary gain-of-function-type effect through ER trapping porting this hypothesis and its consequences on SNCA
and ER-associated degradation process (ERAD). Even more accumulation was provided from cell and animal model
importantly, neither the loss- nor gain-of-function hypotheses studies examining the effect of GBA1 inhibition by CBE
explain why the majority of individuals with GBA1 muta- (Manning-Bo g et al. 2009; Cleeter et al. 2013). Namely,
tions do not develop PD. treatment of differentiated SH-SY5Y cells with CBE resulted
in increased levels of SNCA (Manning-Bo g et al. 2009;
Cleeter et al. 2013). Single injection of CBE led to about
GCase and alpha-synuclein
20% increase in SNCA levels in the ventral mesencephalon
PD-GBA1 belongs to a group of diseases collectively known of normal mice. Also, enhanced SNCA immunoreactivity
as synucleinopathies, which are characterized by the pres- was observed within the cell bodies of the substantia nigra
ence of Lewy bodies and neurites containing SNCA. The pars compacta and within the cytoplasm and cell nuclei of
importance of SNCA in the pathology of PD-GBA1 A9 neurons of CBE-treated mice (Manning-Bo g et al. 2009).
prompted a question about the GCase and SNCA relation- Finally, SNCA accumulation and SNCA oligomer formation
ship. To date, three main hypotheses linking GCase with was shown in a mouse model carrying homozygous knock-
alpha-synuclein have been suggested. out of Gba1, i.e. in mice modeling loss-of-function of GCase
The first proposes that a gain-of-function by the misfolded (Osellame et al. 2013).
GCase results in its direct interaction with alpha-synuclein, The third hypothesis proposes the existence of a bidirec-
which then leads to increased SNCA accumulation and tional feedback loop in which GCase deficiency facilitates
aggregation (Sidransky and Lopez 2012). This would require formation of alpha-synuclein oligomers, with the subsequent
that GCase is able to interact directly with SNCA, and that increase in alpha-synuclein oligomers leading to further
GCase is present in abnormal protein aggregates containing decrease in normal GCase activity, which in turn promotes
SNCA, such as Lewy bodies. Indeed, direct interaction formation of additional alpha-synuclein oligomers (Mazzulli
between GCase and the C-terminus of SNCA was shown to et al. 2011). It has also been demonstrated in cell models that
occur in lysosomes (Yap et al. 2011). The presence of GCase increased alpha-synuclein causes a decrease in GCase
in the brain tissues samples from PD-GBA1 patients was activity and protein levels, as over-expression of exogenous
detected in 32–90% of Lewy bodies and neurites, showing SNCA in SH-SY5Y cell lines resulted in about 44–70%
that mutant GCase and SNCA co-localize in vivo (Goker- decrease in GCase activity, and about 33–87% decrease in
Alpan et al. 2010). One piece of evidence supporting a gain- GCase protein levels (Gegg et al. 2012).
of-function by the misfolded GCase was provided by a cell Finally, although a majority of the studies conducted to
model study, where over-expression of mutant GCase date provide a link between GCase and SNCA via loss-,
(containing N370S, L444P, D409H, D409V, E235A, or gain-of function, or bidirectional feedback loop, some studies
E340A) in neural MES23.6 and pheochromocytoma (PC12) failed to support the relationship between SNCA and mutant
cells led to a 21 to 148% increase in SNCA levels (Cullen GCase. The first such study showed that GBA1 inhibition by
et al. 2011). The relationship between misfolded GCase and CBE in both differentiated SH-SY5Y cells and rat cortical
SNCA was further strengthened by animal model studies. neuronal cultures did not significantly increase SNCA
Namely, a progressive increase in SNCA levels was shown accumulation (Dermentzaki et al. 2013). This contradicts
in the hippocampus of a homozygous D409V Gba1 mouse the results obtained by others, which showed an increase in
model, and a significant increase in SNCA levels was SNCA levels in CBE-treated differentiated SH-SY5Y cells
detected in the forebrain and cerebellum of hypomorphic (Manning-Bo g et al. 2009; Cleeter et al. 2013). This differ-
prosaposin mice carrying the homozygous V394L Gba1 ence may simply have been due to the shorter exposure in the
mutation (Cullen et al. 2011; Sardi et al. 2013). Also, a Dermentzaki study. The second such study demonstrated that
progressive increase in SNCA levels, from low levels to GBA1 inhibition by CBE in PC12 cell line did not alter
substantial SNCA aggregates, was observed in the cortex of SNCA levels, and that over-expression of human wild-type
hypomorphic prosaposin mice carrying the homozygous GBA1 did not lead to an increase in SNCA levels in neural
D409H Gba1 mutation (Xu et al. 2014). MES23.5 cell line. The same study, however, showed that
The second hypothesis proposes that a loss-of-function of over-expression of wild-type GBA1 in HEK293-SNCA
GCase (GCase deficiency because of, for example, degrada- [A53T] and PC12 cell lines resulted in decrease of SNCA
tion of the misfolded enzyme) leads to accumulation of a levels, and that over-expression of different mutant GCase in
substrate (glucocerebroside) that in turn perturbs lipid MES23.6 and PC12 cells led to a significant increase in
homeostasis and subsequently affects alpha-synuclein traf- SNCA levels (Cullen et al. 2011). The cell model specificity
ficking, processing, and clearance. This eventually promotes might explain the observed discrepancy in the effect of over-
alpha-synuclein aggregation and facilitates alpha-synuclein expression of wild-type GBA1 on SNCA levels.
Altogether, although convincing evidence supporting the whether mitochondrial dysfunction is also present in
relationship between SNCA and both gain- and loss-of- PD-GBA1 brains.
function of mutant GCase exists, neither of them explains
why only a proportion of individuals with GBA1 mutations
GCase and autophagy
develop PD. One plausible explanation might be that in order
to develop PD-GBA1, in addition to the GBA1 mutation, Autophagy is a lysosomal pathway that is involved in
there must be additional genetic alternations. Another degradation of damaged organelles, such as mitochondria
credible explanation might be that mutated GCase on its and endoplasmic reticulum, and clearance of long-lived
own is not sufficient to induce alpha-synuclein pathology: misfolded or aggregated proteins, such as alpha-synuclein.
perhaps only when other changes occur (e.g. a perturbation Three distinct types of autophagy have been identified:
of a component of the lysosomal degradation pathway macroautophagy, microautophagy, and chaperone-mediated
resulting in defective SNCA clearance) can PD-GBA1 autophagy (CMA). Increasing evidence indicates the exis-
develop. tence of a strong link between impairment of autophagy and
PD. Dysfunction of autophagy has been shown both in brain
tissue samples from idiopathic PD patients and toxic mouse
GCase and mitochondria
models of PD (Chu et al. 2009; Alvarez-Erviti et al. 2010;
Mitochondria not only play a central role in energy production Dehay et al. 2010; Vila et al. 2011). Although involvement
by oxidative phosphorylation but are also involved in many of autophagic impairment in the development of GD and
other cellular processes, such as synthesis of steroids and especially PD is not yet fully understood, emerging data
regulation of calcium homeostasis, membrane potential, clearly suggest its importance.
apoptosis, and stress response. Taking into account the Lysosomal dysfunction resulting in progressive accu-
plethora of mitochondrial functions, perhaps not surprisingly, mulation of glucocerebroside plays a central role in GD
mitochondrial impairment plays an important role in the pathogenesis. Accumulation of sphingolipids, to which
pathogenesis of PD (Schapira et al. 1989, 1990). In neurons, glucocerebroside belongs, has been shown to alter autophagy
mechanistically, accumulation of dysfunctional mitochondria by both inducing cell death and reducing autophagosome
results in generation of reactive oxygen species and free clearance, and so promoting their accumulation (Tamboli
radicals leading eventually to neuronal death. Mutations in et al. 2011). Indeed, induction of autophagy has been demon-
PARK2, PINK1, and Parkinson protein 7 (PARK7 or DJ-1) strated in GD human fibroblasts that showed accumulation of
genes, which affect mitochondrial morphology and function, glucocerebroside, while increased number of autophagosomes
have been identified as causing familial PD (Schapira 2008). has been shown in hypomorphic prosaposin mice carrying the
However, the role of mitochondrial dysfunction in the homozygous V394L Gba1 mutation that showed accumula-
pathogenesis of PD-GBA1 remains elusive and, to date, only tion of glucocerebroside (Sun et al. 2010a,b; Vaccaro et al.
three studies have investigated the impact of GBA1 mutations 2010). However, it seems unlikely that the autophagic
on mitochondrial function. The first study showed that dysfunction in PD-GBA1 is because of accumulation of
inhibition of GBA1 by CBE in SHSY-5Y cells led to a glucocerebroside (and glucosphingosine, a deacetylated glu-
decrease in adenosine diphosphate phosphorylation, decline in cocerebroside), since substrate accumulation is believed to
mitochondrial membrane potential, and increase in free radical require both GBA1 alleles to carry a genetic alteration, and this
generation, so demonstrating that GCase loss-of-function is not the case in the majority of PD-GBA1 individuals.
causes oxidative stress and mitochondrial dysfunction (Cleeter Analysis of putamen and cerebellum samples from PD-GBA1
et al. 2013). The second study showed that loss-of-function of patients supports that notion, as no accumulation of gluco-
GCase in a mouse model carrying homozygous knock-out of cerebroside and glucosphingosine was observed in these brain
GBA1 resulted in accumulation of dysfunctional and frag- regions (Gegg et al. 2015). In contrast, significantly increased
mented mitochondria, and reduction in respiratory chain glucosphingosine levels (and significantly reduced GCase
complex activities, membrane potential, and oxygen con- activity) were detected in the substantia nigra and hippocam-
sumption (Osellame et al. 2013). The third study showed that pus of idiopathic PD patients during sixth and seventh decade
gain-of-function of GCase in hypomorphic prosaposin mice of life, respectively (Rocha et al. 2015). However, no changes
carrying homozygous D409H or V394L Gba1 mutation led to in glucosphingosine levels were observed in the putamen and
significant reduction in oxygen consumption and mitochon- cerebellum of idiopathic PD patients, although a significant
drial adenosine triphosphate (ATP) production. The same reduction in GCase activity was observed in these regions
findings were also observed in wild-type cerebral cortical (Gegg et al. 2015; Rocha et al. 2015). The observed discrep-
neural cells treated with CBE (Xu et al. 2014). Altogether, ancy in glucosphingosine accumulation among different brain
data from cell and animal model studies demonstrated that both regions should prompt further analysis in both of PD-GBA1
loss- and gain-of-function GBA1 mutations cause mitochon- and idiopathic PD patients to establish whether the relationship
drial impairment, and so it would be worth investigating between reduction of GCase activity and accumulation of
glucosphingosine exists, and, if indeed there is such a link that GD severity shows correlation with levels of misfolded
whether autophagic dysfunction should be at least partially GCase retention in the ER and so, speculatively, with ER
attributed to GCase substrate accumulation. stress (Ron and Horowitz 2005). Biochemical analysis of
The relationship between SNCA and both gain- and loss-of- PD-GBA1 putamen samples for the presence of UPR markers
function of mutant GCase provides a plausible explanation showed a 63% increase in C/EBP homologous protein levels
linking autophagic impairment with PD-GBA1. It has been and a 26% increase in binding immunoglobulin protein. The
shown that SNCA is preferentially degraded by CMA, and that observed UPR/ERAD could be caused by misfolded GCase,
impairment of CMA leads to accumulation and aggregation of but other causes such as oxidative stress, mitochondrial
SNCA in SH-SY5Y cell lines (Alvarez-Erviti et al. 2010). dysfunction, proteolysis, or altered calcium homeostasis
Conversely, it has been demonstrated that expression of mutant cannot be excluded (Gegg et al. 2012). The direct interaction
SNCA leads to CMA impairment in proliferating PC12 and of misfolded GCase with parkin, and its subsequent ERAD
SH-SY5Y cells, while over-expression of wild-type SNCA degradation, has been observed in human COS7 and
results in CMA dysfunction in differentiated SH-SY5Y cells HEK293 cells, providing evidence for the existence of a
(Xilouri et al. 2009). The latter observation is especially direct link between PD-GBA1 and ERAD. Misfolded GCase-
interesting, as misfolded GCase has been shown to facilitate parkin interaction can block parkin interaction with other
SNCA accumulation and aggregation (Mazzulli et al. 2011; protein that are degraded via parkin-mediated ERAD, which
Westbroek et al. 2011; Sidransky and Lopez 2012), and so it would result in further accumulation of proteins in the ER
can be speculated that SNCA increase because of GCase and a further increase in ER stress that would consequently
dysfunction might lead to CMA impairment. Thus, finding a result in neuronal death, and so PD development (Ron et al.
therapeutic agent that is able to increase levels of functional, 2010). In contrast to human studies, analysis of UPR markers
properly folded GCase would enhance SNCA degradation by in the neuronal cultures and tissues obtained from transgenic
CMA, and consequently lead to reduction in SNCA levels. GD mouse models and CBE-treated normal mice showed no
alternations in C/EBP homologous protein, binding
immunoglobulin protein, and X-box binding protein 1
GCase and endoplasmic reticulum stress
(XBP1) (Farfel-Becker et al. 2009). Further studies are
Secretory and membrane-associated proteins are synthetized required to establish whether ER stress really contributes to
in the endoplasmic reticulum and newly synthetized proteins the pathogenesis of PD-GBA1.
are folded in the ER with the help of ER chaperones. Proteins
that fail to fold correctly are recognized by the ER quality
PD-GBA1 treatment
control system and retained for refolding. Misfolded proteins
that fail to refold by ER chaperones are disposed of by There is no specific treatment available for PD-GBA1 patients
ERAD via the ubiquitin–proteasome system. When the to modify the course of the disease. Since nigral dopamine loss
number of misfolded proteins exceeds the capacity of the observed in individuals with PD-GBA1 is identical to that
ERAD system, misfolded proteins accumulate in the ER observed in individuals with idiopathic PD, PD-GBA1 patients
causing stress. In response to such stress, the unfolded are normally given dopaminergic therapy to alleviate the
protein response (UPR) is activated to help restore normal dopamine deficit in the striatum. Therefore, the development
cell function. If this fails, and ER stress continues, malfunc- of new therapies that can slow down disease progression is
tioning cells are eliminated by apoptosis (Yoshida 2007). urgently required. The increasing evidence linking GCase with
Emerging evidence shows the involvement of ER stress in alpha-synuclein and mitochondrial pathways has relevance to
the pathogenesis of PD (Imai et al. 2001; Ryu et al. 2002). a potential novel therapeutic strategy for both PD-GBA1 and
The direct link between ER stress and PD comes from studies idiopathic PD patients. Moreover, even patients without GBA1
of parkin (PARK2), which in mutated form causes early mutations show significant reduction in GCase activity in the
onset of PD. Parkin, an E3 ubiquitin ligase is a member of substantia nigra (Gegg et al. 2012). This highlights the
the UPR, where it is responsible for ubiquitination of importance of GCase function, not only in PD-GBA1 but also
misfolded proteins for degradation. Clearance of misfolded in idiopathic PD and suggests that GBA1 treatments may
proteins is impaired when parkin is mutated, which eventu- potentially prove to be effective with many, if not all, PD
ally results in ER stress (Imai et al. 2000, 2001). The link patients (Schapira and Gegg 2013). The use of small molecular
between misfolded GCase and ER stress is very plausible, as chaperones such as N-(n-nonyl)deoxynojirimycin, isofago-
prolonged accumulation of misfolded GCase in the ER mine, pyrazolopyrimidines, or ambroxol (i.e. the same chap-
would eventually cause ER stress and UPR activation. erones that are currently being tested for their application in
Misfolded GCases, including N370S and L444P mutants, treating GD) may be of interest as a novel therapy for PD, as a
have been shown to be retained in the ER and undergo means to decrease alpha-synuclein levels and improve mito-
ERAD in human GD fibroblasts (Ron and Horowitz 2005; chondrial function (Sawkar et al. 2002; Steet et al. 2006;
Bendikov-Bar et al. 2011). Moreover, it has been reported Maegawa et al. 2009; Bendikov-Bar et al. 2011, 2013;
Patnaik et al. 2012; Luan et al. 2013; Sanders et al. 2013; Alvarez-Erviti L., Rodriguez-Oroz M. C., Cooper J. M., Caballero C.,
McNeill et al. 2014). Interestingly, the benefits of increasing Ferrer I., Obeso J. A. and Schapira A. H. (2010) Chaperone-
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Acknowledgments and conflict of interest Bronstein S., Karpati M. and Peleg L. (2014) An update of Gaucher
disclosure mutations distribution in the Ashkenazi Jewish population:
prevalence and country of origin of the mutation R496H. Isr.
This work was supported by the Medical Research Council (MRC) Med. Assoc. J. 16, 683–685.
grant (MR/M006646/1), Javon Trust grant, Parkinson’s UK (PUK) Bultron G., Kacena K., Pearson D., Boxer M., Yang R., Sathe S.,
grant (G1403) and National Institute of Healthcare Research (NIHR) Pastores G. and Mistry P. K. (2010) The risk of Parkinson’s disease
grant (RCF30AS2012, RCF73TS20145989 and RCF103/AS/2014). in type 1 Gaucher disease. J. Inherit. Metab. Dis. 33, 167–173.
AHVS is a National Institute of Healthcare Research (NIHR) Senior Choi J. M., Kim W. C., Lyoo C. H. et al. (2012) Association of
Investigator. The authors declare that there are no conflicts of mutations in the glucocerebrosidase gene with Parkinson disease in
interest. a Korean population. Neurosci. Lett. 514, 12–15.
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JOURNAL OF NEUROCHEMISTRY | 2016 | 139 (Suppl. 1) | 77–90 doi: 10.1111/jnc.

Department of Clinical Neurosciences, UCL Institute of Neurology, London, UK

Abstract PD-GBA1 is identical to idiopathic PD, with nigral dopamine

Glucocerebrosidase 1 gene Northern blot analysis revealed the existence of at least

Number % with mutation

PD Control PD Control Most common

Number % with mutation

Mde et al. 2013

Clark et al. 2007

Sato et al. 2005

of PD is still unknown. However, given that clinical

in idiopathic PD, alpha-synuclein accumulation, mitochon-

drial impairment, autophagic dysfunction, inﬂammation, and

oxidative and endoplasmic reticulum stress may play an

homozygous mutations in PARK2, PINK1, or DJ-1) and

autosomal dominant forms of PD (caused by heterozygous

mutations in alpha-synuclein (SNCA) or leucine-rich repeat

autosomal dominant modes of inheritance (Sidransky 2012).

Genotyping for L444P and N370S mutations

characteristics of GBA1 suggest loss-of-function of mutated

• A subset of PD-GBA1 patients is identiﬁed with null

et al. 2008; Clark et al. 2009).

to mitochondrial dysfunction, and lipid and alpha-

Autosomal dominant inheritance is often associated with

Most PD-GBA1 patients are identiﬁed with heterozygous

The missense mutations resulting in production of

which subsequently leads to increased alpha-synuclein

Even though there is evidence supporting loss- and gain-

of-function of GCase, both hypotheses have limitations, as

presence of null mutations in some PD-GBA1 patients

contradicts the gain-of-function theory, while development

of PD-GBA1 in individuals carrying heterozygous GBA1

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