Journal of Neurochemistry, 2006, 97, 16901699

SPECIAL ISSUE

doi:10.1111/j.1471-4159.2006.03979.x

The genetics of neurodegenerative diseases

REVIEW

John Hardy*, and Harry Orr

*Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA
Reta Lila Weston Institute of Neurological Studies, The National Hospital for Neurology and
Neurosurgery, London, UK
Department of Biochemistry, Molecular Biology, Biophysics, Department of Laboratory Medicine and
Pathology and the Institute of Human Genetics, The University of Minnesota, Minneapolis, USA

Abstract
In the last 50 years, an enormous amount of progress has
been made in dissecting the etiology of hereditary neurodegenerative diseases, including the dementias, the parkinsonisms, the ataxias and the motor-neuron diseases. In addition,
these genetic findings are beginning to provide insights into
the pathogeneses of the sporadic forms of the diseases.
Through animal and cellular modeling studies we are begin-

ning to gain insights into the pathogenic pathways to disease.

This mechanistic understanding is now leading to therapeutic
strategies based on this new understanding. As yet, however,
no mechanistic therapies are in use in the clinic.
Keywords: ataxia, dementia, parkinsonism, polyglutamine,
a-synuclein, tau.
J. Neurochem. (2006) 97, 16901699.

In our aging societies, neurodegenerative diseases are among

those most feared. In the developed world, they afict about
2% of the population at any time. In many cases genetics
plays a role in their etiology. Studying the genetics of
diseases is important for several reasons: rst, each time a
mutation is identied in a family, it potentially has a direct
clinical impact on that family in terms of diagnosis and presymptomatic and prenatal testing; second, the identication
of pathogenic loci leads to a greater understanding of the
pathogenesis of the disease in general, not just the simple
genetic form of the disease, and thus offers target pathways
for therapy; third, it leads to the development of animal
models of the disease that can be used to develop ideas about
pathogenesis and to test therapies on; and fourth, it gives
direct insight into gene and protein function. An unanticipated bonus from the study of the genetics of neurodegenerative diseases has been the realization that many of these
diseases fall into one of three, or possibly four, classes of
diseases that almost certainly share pathogenic mechanisms,
including the deposition of misfolded proteins, and may
therefore be treatable using similar approaches.
In this review, we discuss these genetic ndings in these
four classes of neurodegenerative disease and the implications of these ndings for the development of ideas
concerning pathogenesis and disease-modifying treatments.
The disease classes include, rst, the tauopathies, second, the

synucleinopathies, a third possible class is the ubiquitin

inclusion diseases and fourth are the polyglutamine diseases.
In each of these families of diseases, the pathway to cell
death is probably broadly similar and offers a therapeutic
target suitable for all of them.

1690

The tauopathies

Either tangle or other tau pathology is found in a large variety

of neurological diseases (Table 1, Lee et al. 2001).
Received April 5, 2006; revised manuscript received April 25, 2006;
accepted April 25, 2006.
Address correspondence and reprint requests to John Hardy, Laboratory
of Neurogenetics, National Institute on Aging, Porter Neuroscience
Building, 35 Convent Drive, Bethesda, MD20892, USA.
E-mail: [email protected]
Abbreviations used: ALS, amyotropic lateral sclerosis; APP, amyloid-b
precursor protein; AR, androgen receptor; BDNF, brain-derived neutrophic factors; CBD, corticobasal degeneration; FTD, frontal temporal
dementia; FTDP-17T, FTD with parkinsonism linked to chromosome 17;
HD, Huntingtons disease; MJD, Machado Joseph disease; PDC, Parkinsons disease/ALS complex of Guam; PEP, von Ecomonos disease
(post-encephalitic parkinsonism); PS1/2, presenilin 1 and presenilin 2
genes; PSP, progressive supranuclear palsy; SBMA, spinobulbar muscular atrophy; SCA1, spinocerebellar ataxia type 1; SCA3, SCA type 3;
SOD, superoxide dismutase; SSPE, subacute sclerosing panencephalitis;
VCP, valosin-containing protein.

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Genetics of neurodegenerative diseases 1691

Table 1 Diseases with Tau Pathology

Alzheimers disease
Argyrophilic grain dementia
Corticobasal degeneration
Dementia pugilistica
Frontotemporal dementia with parkinsonism linked to chromosome
17 (Picks Disease)
Hallervorden-Spatz disease

seen in the context of a neurodegenerative process the tau

dysfunction contributes to the cell loss.
Tangle formation and neurodegeneration has been modeled in transgenic mice carrying MAPT mutations (Hutton
et al. 2001). These mice are thus useful in testing prospective
therapies for tauopathies: for example, lithium treatment,
which inhibits tau phosphorylation, reduces tangle formation
and cell loss in these animals (Noble et al. 2005) and thus
has been proposed as a therapy for tangle diseases.

Myotonic dystrophy
Niemann-Pick disease, type C
Parkinsonismdementia complex of Guam
Postencephalitic parkinsonism
Prion diseases (some)
Progressive subcortical gliosis
Progressive supranuclear palsy
Subacute sclerosing panencephalitis

Although the most common tauopathy is Alzheimers

disease, the prototypic tau disease is frontal temporal dementia
with parkinsonism linked to chromosome 17 (FTDP-17T).
FTDP-17T
Both the clinical and pathological phenotype of FTDP-17T is
remarkably variable. The disease can appear either as a purely
dementing syndrome or present parkinsonian or even amyotrophic features. Tau pathology always occurs, but varies from
wispy tau laments, through Pick bodies to neurobrillary
tangles. In this disease, mutations in either the open reading
frame or in exon-10 splice elements of the tau (MAPT) gene
lead to tau pathology and to neurodegeneration (Hutton 2001).
The precise pathology appears to be largely determined by the
particular MAPT mutation (Ingram and Spillantini 2002;
http://www.molgen.ua.ac.be/ADMutations/default.cfm?MT
1&ML 1&Page MutByGene), with, in general, mutations in the exon-10 splice elements leading to the deposition
of wispy tau laments, mutations in exon 10 leading to dense
deposits of four-repeat tau, and mutations elsewhere in the
MAPT gene leading either to deposits of both three- and fourrepeat tau or to deposits of three-repeat tau in Pick bodies
(Ingram and Spillantini 2002; Sergeant et al. 2005). The
relationship of the mutation to the clinical phenotype is less
clear. The mechanism by which the mutations lead to disease is
also not clear. There are two main theories, which are not
mutually exclusive: either the mutations lead to decreased
microtubule binding, and thus to a greater opportunity for selfaggregation, or they lead to increased self-aggregation and thus
to less microtubule binding (Hutton 2001; Lee et al. 2001;
Ingram and Spillantini 2002). Whatever the precise mechanism of pathogenesis, these data show that tau mutations lead
directly to neurodegeneration and that tau deposition, either as
tangles or Pick bodies is associated with this neurodegenerative process. These ndings have importance beyond FTDP17T families, in that they imply that whenever tau pathology is

Progressive supranuclear palsy (PSP) and corticobasal

degeneration (CBD)
PSP and CBD are relatively rare sporadic diseases characterized by neurobrillary tangles consisting largely of fourrepeat tau (Sergeant et al. 2005). In Europeans the MAPT
gene has an unusual genetic structure, with a very divergent
and inverted H2 haplotype that has an allele frequency of

25% (Evans et al. 2004; Stefansson et al. 2005). This has
made the genetic analysis of PSP and CBD easy in this
population and has shown a robust association between the
H1 haplotype of the MAPT locus and both PSP and CBD
(Hutton 2001). It is likely that there will be a MAPT
association with these diseases in other populations, but the
relevant analyses are more difcult to perform in these other
populations because of the absence of the H2 haplotype. A
haplotypic association, in the absence of coding changes,
implies that the biological effect is mediated by either
differences in expression or differences in splicing between
haplotypes. The fact that the splicing of the MAPT gene is
one of the causes of FTDP-17T, and the fact that the tangle
deposits are, almost exclusively, of four-repeat tau, suggests
that either or both of the above are equally likely explanations. A more detailed analysis of the structure of the H1
haplotype revealed that it has considerable complexity, and
that, in fact, the haplotypic association between H1 and PSP
and CBD is driven by a variant of the haplotype named H1c,
which runs from the promoter to intron 10 of the gene.
Analysis of this haplotype has not yet allowed the determination of whether it is a particularly high-expressing haplotype, one that particularly expresses the exon-10 containing
transcript, or a mixture of both. This haplotypic association is
an example of the general principle that genetic variability at
the loci causing autosomal dominant disease (in this case
FTDP-17T) is part of the genetic contribution to the sporadic
diseases (in this case PSP and CBD) (Singleton et al. 2004).
Parkinsons disease/ALS complex of Guam (PDC), von
Ecomonos disease (post-encephalitic parkinsonism)
(PEP) and subacute sclerosing panencephalitis (SSPE)
When US military medical personnel arrived in Guam
shortly after the World War 2, they were astonished to nd
that, in the southern village of Umatac, amyotropic lateral
sclerosis, ALS (for which the Chamorro word was lytico,
from the Spanish for paralysis) was a major cause of death

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1692 J. Hardy and H. Orr

(Mulder et al. 1954). Later, they realized that a parkinsonian

syndrome (for which the local word was bodig from the
Chamorro word for shufe) was also highly prevalent in the
local community (Kurland et al. 1961). Both diseases were
familial. Neuropathological examination revealed that both
diseases were underpinned by extensive tangle pathology
(Kurland et al. 1961). However, since that time, both
diseases have gradually disappeared and now, although there
are still a few elderly individuals with bodig, lytico has
essentially disappeared and neither disease has convincingly
occurred in an individual born since the turmoil when Guam
was liberated in 1944 (Waring et al. 2004). The disease has
occurred in Chamorros who moved overseas, but not
convincingly in immigrants to Guam. Although it was
familial, the fact that it has died out suggests that it was not a
simple genetic disorder, and indeed a genetic linkage scan
showed that the disease was not a single-gene disorder
(Morris et al. 2004). However, it seems that, like PSP and
CBD, bodig shows an association with the MAPT locus
(Poorkaj et al. 2001) (lytico could not be tested because it
has disappeared). Although there have been many theories
concerning the etiology and pathogenesis of Guam disease,
based on researchers views of the Chamorros diet (Cox and
Sacks 2002), these have not received either epidemiological
or experimental support. Perhaps lytico and bodig most
resemble von Economos disease, which was a parkinsonian
tangle disorder believed to have been caused by a delayed
onset reaction to a viral infection, possibly the 1919 Spanish
u epidemic memorably portrayed in the lm Awakenings
(Dickman 2001). Similarly, SSPE is a rare but serious
complication of measles infection that is also characterized
by tangles (Bancher et al. 1996). These diseases, PDC, PEP
and SSPE, show that although, apart from Alzheimers
disease (discussed below), tangle diseases are rare, they have
the potential to become epidemics: lytico was the major
cause of death in Umatac, and clearly PEP and SSPE have
the potential to reach epidemic proportions given a suitable
infectious agent.
Alzheimers disease
Alzheimers disease is easily the most common neurodegenerative disease and aficts
5% of those over 65 years. It is
characterized clinically by a dementia, classically starting
with problems forming recent memories, and is characterized
pathologically by neuritic plaques of which the peptide Ab42
is the principle component. The autosomal dominant forms
of the disease are caused by mutations in the amyloid-b
precursor protein (APP) and the presenilin 1 and presenilin 2
genes (PS1/2) (Rogaeva 2002). The mutations in APP occur
at its cleavage sites, thereby altering APP processing such
that more Ab42 is produced (Hardy and Selkoe 2002). The
presenilins are a central component of c-secretase, the
enzyme responsible for liberating from the C-terminal
fragment of APP, and mutations in the presenilins also alter

APP processing such that more Ab42 is produced (Wilquet

and De Strooper 2004). These genetic data are the intellectual
basis for the amyloid hypothesis of the disorder, and suggest
that Ab42 is the initiating molecule in Alzheimers disease.
Recent data have reinforced this view, with APP gene
duplications also causing the disease (Rovelet-Lecrux et al.
2006). These genetic data have been largely recapitulated in
transgenic mice. Mice with APP mutant transgenes develop
amyloid plaque pathology, and this pathology is hastened by
crossing them with mice with mutant presenilin transgenes.
However, such mice neither develop extensive cell loss nor
exhibit tangle pathology (LaFerla and Oddo 2005). Crossing
the mice with plaque pathology with the mutant MAPT mice
potentiates the tangle pathology but has no effect on the
plaque pathology, suggesting that the Ab/amyloid pathology
is upstream, in the pathological cascade, to the tau/tangle
pathology (Hardy et al. 1998).
Although there is a consensus that Ab is upstream of tau in
the pathological cascade in Alzheimers disease, there is little
hard evidence on either the nature of the interaction or how
direct it is. The most promising line of enquiry in this regard
is the observation that Ab was much less toxic to neurons in
which the MAPT gene had been knocked out (Rapoport et al.
2002). The nature of the toxic species of Ab is also not
entirely clear, but an evolving view has been that it is some
form of Ab oligomer: this evolving consensus has centred
around a species called A4 in the original APP cloning paper,
or more recently Alzheimers Disease Diffusible Ligands, Ab
oligomers or Ab* (Klein et al. 2004). Strictly, these species
have not been shown to be toxic, but rather have been shown
to be potent synaptic depressants (Lesne et al. 2006).
Much of the effort for developing mechanistic therapeutics
has been aimed at APP processing (Fig. 1): by inhibiting
either BACE or c-secretase either directly or indirectly
(Hardy and Selkoe 2002; Golde 2005). The greatest publicity
has been given to trials of immunization against Ab. This
immunization clearly and surprisingly results in the clearance
of Ab from the brains of mice and humans, and has
behavioral benets in the mice, but the human trial resulted in
serious and occasionally fatal meningoencephalitis in a
proportion of Alzheimer cases without clear clinical benet
(Schenk et al. 2004). Whether this was an adverse effect of
the particular protocol used or was centrally related to the
immunological approach to Ab clearance is currently unclear.
In the Alzheimer eld there is the general sense that
mechanistic approaches to therapy should emerge soon, but
there is also a growing impatience amongst those who believe
that Ab-centred therapy should have worked by now if indeed
it was a valid approach to the disease (Lee et al. 2005).
The synucleinopathies

Like the tauopathies, a-synuclein pathology is a feature of

many neurodegenerative diseases (Table 2).

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Genetics of neurodegenerative diseases 1693

Indeed there is considerable overlap between the diseases

suggesting that there are mechanistic relationships between
them. This overlap includes, for example, Alzheimers
disease, where a-synuclein pathology occurs in cases with
APP mutations, Downs syndrome and in presenilin mutation cases (Lee et al. 2004: Fig. 2). An analogous interaction
to that between Ab and tau in the APP/MAPT double
transgenic mice alluded to above (Hutton et al. 2001) has
been shown between Ab and a-synuclein in APP/synuclein
double transgenic mice (Hashimoto et al. 2003). In both
cases, the APP transgene potentiates the intracellular
pathology.

Fig. 1 APP processing.

Table 2 Diseases with a-Synuclein Pathology

Alzheimers disease
Gauchers disease
Hallervorden-Spatz disease
Lewy Body Dementia
Multisystem atrophy
Parkinsons disease
Prion diseases (some)

Parkinsons disease
The prototypic synucleinopathy is Parkinsons disease (Spillantini et al. 1997). However, the nosology of Parkinsons
disease is messy (Hardy and Lees 2005). About 90% of
individuals with the clinical diagnosis of Parkinsons disease
have Lewy bodies (Hughes et al. 2001), but there is no
agreement about whether the disease should be dened by
clinicians or as a clinicopathologic entity. This becomes
important because none of the genetic ndings t cleanly
with the diagnoses. Five genes have been identied that
cause mendelian diseases which have been claimed to be
Parkinsons disease (Cookson et al. 2005; Table 3) and in no
case was there a one-for-one mapping of gene defect with the
diagnosis of Lewy Body Parkinsons disease. However,
genetic variability at the a-synuclein locus contributes to the
risk of the sporadic disease, indicating that a-synuclein
expression contributes to the risk of the sporadic disease in
an analogous fashion to tau expression and sporadic tangle
disease (Singleton et al. 2004). Whether all these genetic loci
map onto one pathway to disease analogous to the amyloid

Fig. 2 An outline of the relationship

between Ab, tau and a-synuclein according
to the amyloid hypothesis.

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1694 J. Hardy and H. Orr

Table 3 Loci claimed to cause Parkinsons disease

Gene

Mode of inheritance

Putative function

Problem

a-synuclein

Dominant

Vesicle trafficking?

parkin

Usually recessive

Protein turnover

Some cases have Lewy body dementia rather

than Parkinsons disease clinically
Most cases dont have Lewy bodies

DJ-1

Usually recessive

Signaling to mitochondrion

No pathological reports have been published

PINK1

Usually recessive

Mitochondrial kinase

No pathological reports have been published

LRRK2

Dominant

Cytoplasmic kinase

Pathology usually involves Lewy bodies but sometimes

it is a tangle disease and sometimes there seems to
be no histopathology

Fig. 3 An outline of the putative relationship between dardarin (encoded by

LRRK2) and a-synuclein and tau.

hypothesis for Alzheimers disease remains unclear (AbouSleiman et al. 2006).

The most puzzling gene for Parkinsons disease is LRRK2,
which encodes the protein, dardarin. Mutations in this gene
are a very common cause of typical Lewy body Parkinsons
disease (Gilks et al. 2005), but can also cause tangle
pathology (Zimprich et al. 2004). It is not clear how this
relates to the pathogenesis of these lesions (Singleton 2005),
although in this respect one could think of LRRK2/dardarin
having a similar biochemical effect as an Ab load (Fig. 3 q.v.
Fig. 2). Thus, from a genetic perspective, the mutations in
LRRK2, which appear to be a gain of kinase function (West
et al. 2005), have a similar action to Ab suggesting that
dardarin may be on the pathway from Ab to tau and
synuclein.
In terms of mechanistic treatment, perhaps the two most
promising approaches are synuclein immunization, which
remarkably cleared intraneuronal synuclein pathology in the
transgenic mice (Masliah et al. 2005), and developing an
inhibitor for dardarin, as the pathogenic mutations seem to
lead to overactive kinases.

The ubiquitin-inclusion diseases

For the tauopathies, the synucleinopathies and the polyglutamine diseases, molecular histochemistry has shown that the
lesions in the different diseases are essentially identical,
suggesting that their pathogenesis is probably also very
similar. This is not true for the ubiquitin-inclusion diseases
for which the molecular substrate is not yet known, and so
designation of this as a class of diseases is not as certain as
for the other diseases.
Two genetic loci have been reported for this disease,
frontal temporal dementia (FTD) on chromosome 17, close
to the MAPT locus and FTD/ALS on chromosome 9p.
FTDP-17U
Remarkably, a proportion of families that showed genetic
linkage to chromosome-17 markers did not have MAPT
mutations, although their clinical features were indistinguishable from those that did (Foster et al. 1997; van der Zee et al.
2006). At autopsy, these cases have no tangle pathology,
but rather had ubiquitin-positive inclusions (Mackenzie
et al. 2006). The majority of cases that show this linkage

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Genetics of neurodegenerative diseases 1695

have FTD, although a minority have an ALS presentation. It

will not be entirely clear how prevalent this condition is until
the gene is identied, but a recent study from Flanders
suggested it may be quite common (van der Zee et al. 2006).
It seems a remarkable coincidence that this locus should
map essentially to the same point on the genome to FTDP17T, and yet, apparently, be pathogenically distinct. Only
when the gene is identied will we be able to determine
whether its function relates to tau biology (Hardy et al.
2006).
FTD/ALS chromosome-9p linked
Recently, linkage to markers on chromosome 9p has been
independently reported by two groups (Morita et al. 2006;
Vance et al. 2006): this linkage apparently supersedes
previous reports of linkages to chromosome 9q and 16q
markers (ibid.). The phenotype of these families includes
both FTD and ALS, and the pathology is again of
ubiqitinated inclusions.
Inclusion body myopathy associated with Paget disease
This rare disease classically has an unusual mixture of
features of Pagets disease of bone and a progressive
dementia. Genetic analysis linked it to chromosome 9p
(although to a separate location from the FTD/ALS syndrome described above). The locus was identied as the
valosin-containing protein (VCP), an AAA-ATPase that is
believed to be involved in the ubiquitin proteasome pathway
(Watts et al. 2004). In some individuals, the phenotype is of
a pure FTD, and the pathology is also of ubiquitinated
inclusions (Schroder et al. 2005). These ubiquitinated inclusions also stain for VCP.
ALS
Interestingly, most cases of ALS, but not those with
superoxide dismutase 1 (SOD1) mutations, have ubiquitinated inclusions (Leigh et al. 1991; Mackenzie and Feldman

2005). This implies that typical ALS may have a pathogenesis related to this pathway, but that the SOD-encoded ALS
represents a different pathogenesis. From a treatment
perspective, because the SOD mutant mice are typically
used to test therapies, it is important to determine whether
they do indeed share the same pathogenesis or whether the
grouping of diseases should rather be as outlined herein.
The polyglutamine diseases

The group of inherited neurodegenerative diseases designated the polyglutamine diseases share many seminal features
with the other families of neurodegenerative diseases
(Zoghbi and Orr 2000). They typically manifest with a late
age of onset and, at least during their initial stages, these
disorders are characterized by a specic set of clinical signs
with pathology limited to a distinct subset of neurons. Like
many other neurodegenerative diseases, the polyglutamine
diseases have, as a hallmark of pathology, the accumulation
of insoluble material within neurons, adding further to the
concept of a common pathogenic theme, the generation and
accumulation of misfolded proteins. Whether the polyglutamine inclusions have a direct role in pathogenesis remains
controversial.
Nine neurodegenerative diseases have as their diseasecausing mutation the expansion of a polyglutamine tract
(polyQ). This involves the unstable expansion of a CAG
sequence within the coding region of each gene. Thus,
these diseases fall within a broader class of disorders, i.e.
diseases that involve the expansion of an unstable
repetitive element, usually triplet sequences (Gatchel and
Zoghbi 2005). Interestingly, expansions of an unstable
nucleotide repeat is a mutational mechanism that appears
to be unique to the human genome. Furthermore, although
genes that are highly homologous to the polyglutamine
genes are present in the genomes of other mammals, the
polyglutamine tract is not conserved (Table 4), suggesting

Table 4 CAG repeat lengths in mammalian species

Disease

Gene
Locus

SBMA

Xq1112

Human
wild-type
alleles

Human
mutant
alleles

Chimpanzee

Orangutan

Macaque

Marmoset

Rodent

4063

1823

79

NA

Protein

Protein
Location
Nuclear &
cytoplasmic
Cytoplasmic

639
634

36121

NA

NA

NA

NA

Nuclear (neurons)

844

3983

2026

2025

915

915

HD

4p16.3

Androgen
receptor
Huntingtin

SCA1

6p2223

Ataxin-1

SCA2

12q2324

Ataxin-2

Cytoplasmic

1333

3277

2227

1617

NA

NA

QPQ

SCA3/MJD

14q24.331

Atxain-3

Cytoplasmic

1240

5489

1420

2425

1314

NA

NA

SCA6

19p3

CACNA1A

Cell membrane

418

2133

913

1113

NA

NA

NA

SCA7

3p12p21.1

Ataxin-7

Nuclear

435

37306

NA

NA

NA

NA

NA

SCA17

22q13

TATA-BP

Nuclear

2942

4755

NA

NA

NA

NA

NA

DRPLA

12q

Atrophin-1

Cytoplasmic

636

4984

1117

15

NA

NA

NA

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1696 J. Hardy and H. Orr

that the polyglutamine stretches are not necessary for

normal function.
The polyglutamine disorders include spinobulbar muscular
atrophy, Huntingtons disease (HD), the spinocerebellar
ataxias (SCA1, SCA2, SCA3/MJD, SCA6, SCA7 and
SCA17), and dentatorubral-pallidoluysian atrophy (DRPLA).
All of these disorders are progressive, typically striking at
midlife and having a course that consists of an extended
period of neuronal dysfunction followed by neuronal loss
and eventually death 1020 years after onset. Other features
that characterize this group of neurodegenerative disorders
include a direct relationship between the length of the
polyglutamine tract and the severity of the disease, and
between the number of glutamines and the age of onset and
the severity of the disease. Mutant CAG repeats show both
germline and somatic instability. Germline instability along
with the relationship between repeat length and disease
course are the basis for the phenomena of genetic anticipation. As the repeat grows upon passage from generation to
generation, affected members in successive generations have
an earlier age of onset and more rapidly progressing form of
the disease.
In the following sections some of the polyglutamine
disorders are discussed in more detail. Attention is directed to
the disorders that are more prominent and to other instances
where research suggests insights that may have broader
implications for the neurodegenerative disorders.
Spinobulbar muscular atrophy (SBMA)
SBMA (also known as Kennedys disease) is characterized
by the loss of anterior horn, bulbar motorneurons and dorsal
root ganglia sensory neurons. Except for SBMA, which is
caused by a mutation in the androgen receptor (AR) gene on
the X chromosome, the polyglutamine disorders are inherited
in an autosomal dominant fashion. Yet SBMA is in many
ways the archetypical polyglutamine disease. SBMA was the
rst polyglutamine-based disorder for which the gene was
cloned (La Spada et al. 1991). More importantly the genetics
of AR provide clear evidence that the polyglutamine
expansion is a gain-of-function mutation and not a loss-offunction mutation. SBMA (or Kennedys disease) is an adultonset motorneuron disease with only very limited signs of
androgen insensitivity in adults. A loss of function mutation
in AR does not result in either SBMA or motorneuron
disease. Rather the deletion of the AR gene leads to testicular
feminization, with abnormal fetal sexual development and no
signs of motorneuron disease such as weakness. The distinct
phenotype caused by a loss of AR function compared with
SBMA provides a strong genetic argument that the polyglutamine expansion associated with SBMA is not a loss-offunction mutation. Moreover, the genetics of SBMA indicate
that the pathogenic mechanism triggered by the polyglutamine expansion gain-of-function mutation in AR is linked to
the normal function of this protein. SBMA is essentially a

disorder that affects only males. In fact women who are

homozygosis for expanded CAG repeats in the AR were
reported to have minimal disease, suggesting that a sexspecic factor impacts the expression of SBMA (Schmidt
et al. 2002). It appears that the higher levels of circulating
androgen hormone in males are required for mutant AR to
cause SBMA, connecting the pathogenic pathway of mutant
AR to its normal function.
Recent studies that administered androgen antagonists to a
mouse and Drosophila (y) model of SBMA support the
premise that ligand-induced nuclear translocation of mutant
AR is a crucial aspect of SBMA pathogenesis (Katsuno et al.
2002, 2003; Takeyama et al. 2002). One agent, leuprorelin,
was found to be very effective in rescuing all aspects of the
disease phenotype. Leuprorelin is a luteinizing hormone
releasing hormone agonist that reduces the release of
testosterone from the testis and thereby reduces circulating
levels of testosterone. This result supports the concept that
ligand-induced nuclear translocation of mutant AR is a
crucial aspect of SBMA pathogenesis. The second drug used
to treat the SBMA mice, utamide, had no effect on motor
neuron disease. Flutamide has a very high afnity for AR and
functions as an androgen antagonist by competitively
competing with testosterone for binding to AR. Although
utamide suppresses the androgen-dependent transactivation
activity of AR, it neither reduces plasma testosterone nor
blocks nuclear translocation of mutant AR in either the mouse
or the y. Besides providing an important mechanistic insight
into SBMA, this result suggests that leuprorelin is a
candidate for the treatment of SBMA.
Huntingtons disease (HD)
HD is the most prevalent polyglutamine disease. In addition
to motor symptoms (chorea), HD often presents with
cognitive changes that include memory decits, depression
and changes in personality. Pathologically HD is characterized by the loss of medium-sized spiny GABAergic neurons
from the striatum. There is also a loss of cortical neurons that
project to the striatum.
Transgenic mice expressing a small N-terminal fragment
of huntingtin with an expanded polyglutamine tract develop
abnormal neurological signs and neuropathology (Mangiarini
et al. 1996). This result led to the hypothesis that in HD
pathogenesis a crucial step is the proteolytic production of a
toxic N-terminal fragment from intact mutant huntingtin.
This concept is still widely held with considerable effort
directed at understanding the proteolytic processes that act
upon huntingtin (Tarlac and Storey 2003.). These mice were
also instrumental in bringing to the forefront the inclusion/
aggregate model of HD pathogenesis, as well as the
pathogenesis of polyglutamine diseases in general. After
much study, the concept that large inclusions/aggregates of a
mutant polyglutamine are the pathogenic species seems to
have fallen into disfavor (Arrasate et al. 2004).

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Genetics of neurodegenerative diseases 1697

In regards to specic cellular pathways that might be

targets of the toxic gain-of-function property of mutant
huntingtin (either intact or an N-terminal fragment), three
have gained the most attention: deregulation of transcription
(Sugars and Rubinsztein 2003), disruption of intracellular
trafcking (Gunawardena and Goldstein 2005), and a change
in mitochondrial/energy metabolism (Browne and Beal
2004). An interesting point where a role of huntingtin in
cytoplasmic transport and transcription deregulation might
intersect is centered on the function of brain-derived
neutrophic factors (BDNF). BDNF is a prosurvival factor
for striatal neurons and its levels have been found to be
decreased in HD brains (Ferrer et al. 2000). Two nonexclusive mechanisms that have been suggested for this
decrease are a mutant huntingtin-induced decrease in BDNF
transcription (Zuccato et al. 2001) and an induced transport
decit of BDNF vesicles (Gauthier et al. 2004). More
recently a correlation of [ATP/ADP] with the length of the
polyglutamine tract in intact huntingtin was reported (Seong
et al. 2005). An inverse association throughout the range of
wild-type and mutant polyglutamine tract lengths was found.
This observation suggests that variation in the length of the
polyglutamine tract in huntingtin is by some mechanism a
regulator of the energy status of striatal neurons. If
conrmed, this relationship may underlie the vulnerability
of medium-sized spiny striatal neurons to excitotoxicity,
which would have important implications for HD pathogenesis.
Spinocerebellar ataxia type 1 (SCA1)
SCA1 is one of several inherited forms autosomal dominant
ataxia. Typical of most ataxias, SCA1 consists clinically of
gait ataxia dysarthria and bulbar dysfunction, with death
usually ocurring between 10 and 15 years after the onset of
symptoms. Despite the protein, ataxin-1, being widely
expressed in the CNS, the most frequently seen and most
severe pathological alterations are restricted to loss of
Purkinje cells in the cerebellar cortex, as well as loss of
neurons in the inferior olivary nuclei, the cerebellar dentate
nuclei and the red nuclei.
With the identication of an expanded polyglutamine tract
as the mutational basis for several neurodegenerative disorders, a pathogenic mechanism largely dependent on the
biochemical property of the polyglutamine tract itself gained
quick favor. In contrast, two experiments utilizing SCA1
transgenic mice showed that amino acid residues outside of
the polyglutamine had a crucial role in pathogenesis. In the
rst example an amino acid substitution was made in the
nuclear localization signal of ataxin-1, such that the protein
could no longer be translocated into the nucleus. When this
substitution was placed into a mutant allele of ataxin-1 with
an expanded polyglutamine tract that was then used to
generate transgenic mice, the mice failed to develop disease
(Klement et al. 1998). Thus by restricting the subcellular

distribution of mutant ataxin-1 to the cytoplasm of susceptible neurons the protein was no longer pathogenic. Perhaps a
more dramatic illustration of the importance of host protein
sequence for pathogenesis was shown recently when a site of
phosphorylation of ataxin-1 was identied, the serine at
position 776 (Emamian et al. 2003). Replacing this serine
with an alanine yielded a protein that still was transported to
the nucleus, but when transported in a mutant ataxin-1 with
82 glutamines failed to cause disease.
Spinocerebellar ataxia type 3 (SCA3)/Machado Joseph
disease (MJD)
SCA3, also known as MJD, is the most common of the
autosomal dominantly inherited ataxias. SCA3 has several
genetic features that distinguish it from many of the other
polyglutamine disorders. In contrast to HD and SCA1, where
the repeat threshold for mutant alleles is near 40, in SCA3 the
repeat threshold for mutant alleles is longer than 50 repeats.
Moreover, although other polyglutamine disorders behave as
pure dominant diseases, SCA3/MJD homozygous patients
have a more severe disease presentation than individuals with
only a single mutant allele.
Ataxin-3, the SCA3-encoded polyglutamine protein, is a
polyubiquitin binding protein by virtue of its ubiquitin
interaction motifs (UIMs) located close to the polyglutamine
tract (Burnett et al. 2003; Chai et al. 2004). Ataxin-3 also
has ubiquitin protease activity and interacts with components
of the proteasome complex. These aspects of ataxin-3
provide strong evidence that this protein normally functions
in the ubiquitin-proteasome pathway. Recently in a Drosophila model of SCA3/MJD it was shown that wild-type
ataxin-3 is a suppressor of polyglutamine-induced neurodegeneration (Warrick et al. 2005). This work highlights
further the importance of the link between protein-folding/
clearance pathways and neurodegeneration.
Summary and conclusions

Each of the diseases briey reviewed in this article share

pathogenic mechanisms within their class, and therefore it is
likely that developing an understanding of one member of the
class will help more generally with the entire class of diseases.
However, there are similarities between classes of disease:
most obviously between the tauopathies and the synucleinopathies where there are both genetic parallels and overlap
between the mechanisms by which they can be initiated. In all
of these diseases, the process of protein deposition, if not the
deposits themselves, appear to play a key role in initiating the
disease, suggesting that at a deeper level all of these diseases
may share similarities. A recent suggestion is that there are
oligomeric intermediates with similar properties that mediate
toxicity in all of the diseases (Glabe 2006).
Despite the enormous amount of progress we have made
in terms of understanding the etiologies of these diseases in

2006 International Society for Neurochemistry, J. Neurochem. (2006) 97, 16901699

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1698 J. Hardy and H. Orr

the last 15 years, the most important questions remain

unanswered. What are the mechanisms of cell death in these
diseases? Why does each disease preferentially affect certain
neuronal types? Why do diseases have onset ages from
middle to late life? and of course, most importantly, can we
realize the promise of knowledge-based treatments for these
devastating disorders? Much has been done, but much
remains
Acknowledgements
JH is part of the intramural NIA/NIH program. HO is supported by
the NINDS.

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