Neuromol Med (2016) 18:1–15

DOI 10.1007/s12017-015-8370-x

ORIGINAL PAPER

Does PGC1a/FNDC5/BDNF Elicit the Beneficial Effects

Jennifer Curtiss3 • Mahsa Shirani Faradonbeh2 • Pooneh Vaziri3 •

Received: 10 April 2015 / Accepted: 22 August 2015 / Published online: 26 November 2015
Ó Springer Science+Business Media New York 2015

Abstract Neurodegenerative disorders such as Alzhei- hippocampus. BDNF is secreted from hippocampus,
mer’s, Parkinson’s and Huntington’s diseases have high amygdala, cerebral cortex and hypothalamus neurons and
prevalence among the elderly. Many strategies have been initiates intracellular signaling pathways through TrkB
established to alleviate the symptoms experienced by receptors. These pathways have positive feedback on
affected individuals. Recent studies have shown that CREB activities and lead to enhancement in PGC1a
exercise helps patients with neurological disorders to expression in neurons. Therefore, FNDC5 could behave as
regain lost physical abilities. PGC1a/FNDC5/BDNF has a key regulator in neuronal survival and development. This
emerged recently as a critical pathway for neuroprotection. review presents recent findings on the PGC1a/FNDC5/
PGC1a is a highly conserved co-activator of transcription BDNF pathway and its role in neuroprotection, and dis-
factors that preserves and protects neurons against cusses the controversial promise of irisin as a mediator of
destruction. PGC1a regulates FNDC5 and its processed the positive benefits of exercise.
and secreted peptide Irisin, which has been proposed to
play a critical role in energy expenditure and to promote Keywords BDNF  FNDC5  Irisin  Neuroprotection 
neural differentiation of mouse embryonic stem cells. Neurodegenerative diseases  PGC1a
FNDC5 may also increase the expression of the neu-
rotrophic factor BDNF, a neuroprotective agent, in the Abbreviations
6-OHDA 6-Hydroxy dopamine
Ab Amyloid beta
& Kamran Ghaedi
[email protected]
AD Alzheimer’s disease
ALS Amyotrophic lateral sclerosis
& Timothy L. Megraw
[email protected]
ATP Adenosine triphosphate
BDNF Brain-derived neurotrophic factor
& Mohammad Hossein Nasr-Esfahani
[email protected]
CNS Central nervous system
CREB cAMP-responsive element binding protein
1
Department of Cellular Biotechnology, Cell Science DHA Docosahexaenoicacid
Research Center, Royan Institute for Biotechnology, ERRa Estrogen-related receptor alpha
ACECR, Royan Street, Salman Street, Khorasgan,
Isfahan 8165131378, Iran
ETC Electron transport chain
2
FA Friedreich’s ataxia
Department of Biology, School of Sciences, University of
Isfahan, Hezarjerib Street, Azadi Square,
FNDC5 Fibronectin type III domain-containing 5
Isfahan 8174673441, Iran GPx Glutathione peroxidase
3 HD Huntington’s disease
Department of Biology, New Mexico State University,
Las Cruces, NM, USA KSS Kearns–Sayre syndrome
4 LTP Long-term potentiation
Department of Biomedical Sciences, Florida State University
College of Medicine, West Call Street, Tallahassee, MAO Monoamine oxidase
FL 32306-4300, USA MAPK Mitogen-activated protein kinase

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MELSAS Mitochondrial encephalopathy lactic acidosis context of Parkinson’s disease. One is that exercise protects
and strokes neurons from oxidative stress. The other is that exercise
mHtt Mutant huntingtin protein increases expression of neuronal trophic factors, such as
Mn-SOD Manganese superoxide dismutase BDNF, and other factors that promote survival, mainte-
MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine nance and function of neuronal progenitors and of neuronal
NMDA N-Methyl-D-aspartate tissues in general.
NRF Nuclear respiratory factor
OXPHOS Oxidative phosphorylation system
PARIS Parkin-interacting substrate Mitochondria and Peroxisomes and Oxidative
PBDs Peroxisome biogenesis disorders Stress
PD Parkinson’s disease
PEDs Peroxisomal enzyme deficiencies The pathology of neurodegenerative diseases including
PEP Peroxisomal protein AD, PD and HD have close correlation with oxidative
PGC1a Peroxisome proliferator-activated receptor c stress and the impairment of mitochondrial energy meta-
co-activator a bolism (Tretter et al. 2004; Guo et al. 2013). Oxidative
PI3K Phosphatidyl inositol-3-kinase stress can occur when production of reactive oxygen spe-
PLCc Phospholipase C-c cies (ROS), which include the superoxide anion radical
PPARa Peroxisome proliferator receptor alpha (O2–), hydrogen peroxide (H2O2) and the hydroxyl radical
PUFAs Polyunsaturated fatty acids (–OH), as well as reactive nitrogen species (RNS), which
ROS Reactive oxygen species include the nitric oxide radical (–NO), the nitrogen dioxide
SIRT1 Sirtunin1 radical (–NO2), nitrite (NO2–) and peroxynitrite (ONOO–),
SNP Single-nucleotide polymorphism outpaces a cell’s ability to inactivate ROS/RNS and to
SOD Superoxide dismutase repair damage. ROS/RNS can damage all of the major
TAF4 Transcription initiation factor 4 biomolecules and initiate cell death (Rinnerthaler et al.
TFAM Mitochondrial transcription factor A 2015). Mitochondria and peroxisomes are important sites
TR Thyroid receptor of ROS/RNS production. Mitochondria are the major
TrkB Tyrosine kinase receptor B source of ATP by oxidative phosphorylation (OXPHOS).
VDAC Voltage-dependent anion channels During oxidative phosphorylation, electrons are transferred
from electron donors to electron acceptors in redox reac-
tions. These redox reactions are carried out by the electron
transport chain (ETC), which consists of four discrete
complexes (I–IV) that are embedded in the inner mito-
Introduction chondrial membrane. These complexes generate an elec-
trochemical gradient that is used to drive ATP production.
The prevalence of neurodegenerative disorders such as The last complex (complex IV) in the ETC transfers two
Alzheimer’s disease (AD), Parkinson’s disease (PD) and electrons and two protons to O2, to form water.
Huntington’s disease (HD) increases by age worldwide. The main type of ROS produced during oxidative
Because life expectancy is steadily lengthening so has the phosphorylation is superoxide (O2–), which forms when an
prevalence of these diseases and the critical need for electron is transferred prematurely to O2, chiefly by com-
research directed at finding cures. plexes I and III, though other mechanisms exist (Mailloux
Neurodegenerative disorders result in progressive loss of 2015). Mitochondrial superoxide dismutases (SODs) of the
neuronal structure and/or function (Przedborski et al. 2003; manganese (SOD2) types process superoxide into H2O2, a
Vila and Przedborski 2003). These disorders are charac- less potent ROS, but still capable of causing oxidative
terized by protein misfolding and aggregation, mitochon- damage. Another source of mitochondrial H2O2 that is
drial dysfunction and oxidative stress, and programmed especially important in neurons is monoamine oxidases
cell death of neurons, but what causes the disorders (MAOs), which catalyze the turnover of monoamine neu-
remains a mystery. Physical exercise has been shown to be rotransmitters (serotonin, norepinephrine, dopamine) (Ed-
neuroprotective in the context of several neurodegenerative mondson 2014). The presence of superoxide and H2O2 can
diseases, including AD and PD. However, the mechanisms also lead to production of other ROS/RNS. For instance,
by which physical exercise prevent neurodegenerative superoxide can react with FeS-containing proteins (e.g.,
diseases or improve symptoms in patients with neurode- complex I) to produce Fe2?, which can react via the Fenton
generative diseases are currently unclear. Monteiro-Junior reaction with H2O2 to form the hydroxyl radical (–OH)
et al. (2015) recently put forward two hypotheses in the (Winterbourn 1995). The presence of –OH can initiate a

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cascade of reactions that result in the formation of lipid enriched in myelin. Accordingly, reduction in plasmalogen
radicals and lipid peroxide radicals (Ayala et al. 2014). In levels is correlated with AD severity (Bennett et al. 2013).
addition, a number of mitochondrial enzymes produce Importantly, ROS/RNS production by mitochondria and
nitric oxide (–NO), which can combine in the mitochon- peroxisomes is affected by the metabolic status of the cell.
drial matrix with superoxide (O2–) to form peroxynitrite For instance, ROS production from the ETC increases if,
(ONOO–) (Murphy 2009). The functions of animal per- e.g., glucose and fatty acid levels are high (lots of NADH
oxisomes include b-oxidation of very long chain fatty acids and FADH2 being produced), but energy levels are low
and synthesis of ether-linked phospholipids, both of which (Ruetenik and Barrientos 2015). Accordingly, although the
have relevance for oxidative stress (Antonenkov et al. acute effect of exercise is an increase in ROS production
2010; Fransen et al. 2012; Lodhi and Semenkovich 2014). and oxidative stress, regular exercise leads to induction of
b-Oxidation of fatty acids also occurs in mitochondria in antioxidants, DNA repair and protein-degrading enzymes,
mammals, where electrons produced by the first step of b- thus shifting the balance and decreasing the probability of
oxidation are transferred to FADH to generate FADH2 and oxidative stress (Radak et al. 2005).
subsequently fed into the electron transport chain to pro- In addition to mitochondrial superoxide, cytosolic
duce ATP. In contrast, in peroxisome b-oxidation, FADH2 NADPH oxidase is another major site for superoxide pro-
transfers electrons directly to O2, generating H2O2. b-Ox- duction in the cell. NADPH oxidase is mainly located on
idation in peroxisomes is thought to shorten very long ([26 the cytosolic face of phagocyte membranes and plays a
carbon) chain fatty acids, which can then be further oxi- critical role in immune defense. Microglia, which are the
dized in mitochondria. In addition to the H2O2 produced by phagocytes of the central nervous system (CNS), have high
b-oxidation and other processes, peroxisomes also contain NADPH oxidase activity especially in many neurodegen-
enzymes capable of producing –NO and O2–, and so it is erative diseases. Therefore, activated microglia produce
likely that peroxisomes also contain ONOO–. oxidants that can negatively affect the function of the CNS
Although mitochondria and peroxisomes are major (Bordt and Polster 2014).
sources of ROS/RNS, they are also rich in antioxidants that Although any part of a cell can be affected by oxidative
inactivate ROS/RNS. They can thus serve as either as net stress, oxidative damage in the mitochondria is likely to be
sources or as net sinks of ROS/RNS (Fransen et al. 2012; particularly devastating because it potentially results in a
Andreyev et al. 2015). The mechanisms that exist for feedback loop: The oxidative damage can decrease mito-
inactivating ROS/RNS in mitochondria and peroxisomes chondrial function in ways that result in higher production
include both enzyme and non-enzyme-based systems. The of ROS/RNS, leading to even more damage. Because the
enzyme-based systems include the aforementioned SODs, mitochondrial genome (mtDNA) contains 24 genes
which processes superoxide to form H2O2, as well as encoding tRNAs and rRNAs important for mitochondrial
catalase, glutathione peroxidase (GPx) and peroxiredoxins, protein synthesis, and 13 encoding components of the ETC,
which convert H2O2 to H2O. Non-enzyme-based systems much mitochondrial dysfunction is likely to occur as a
include glutathione (GSH)-based systems (Andreyev et al. result of damage to mitochondria DNA (mtDNA) (Keogh
2015). and Chinnery 2015).
Another way that peroxisome function may protect cells It is likely that mtDNA is particularly susceptible to
against oxidative stress is via production of ether phospho- oxidative damage in part because it lies in the mitochon-
lipids, which contain a fatty alcohol instead of a fatty acid at drial matrix in close proximity with the electron transport
the sn-1 position. Members of the plasmalogen family of chain, which as mentioned above is a major source of ROS.
ether phospholipids are modified to contain a vinyl ether Conditions of cellular stress that impact ROS/RNS pro-
bond, and are enriched at the sn-2 position in the polyun- duction and/or antioxidant efficiency could result in an
saturated fatty acids docosahexaenoic acid (DHA), C22:6 -- increase in mtDNA mutations that could further impact
3 or arachidonic acid C20:4 --6(Braverman and Moser mitochondrial function (Ciccone et al. 2013; Farrar et al.
2012; Lodhi and Semenkovich 2014). The presence of the 2013; Guo et al. 2013; Keogh and Chinnery 2015; Payne
fatty alcohol results in changes in membrane structure in and Chinnery 2015).
plasmalogen-enriched membranes that may affect signaling, The fact that cells contain 100–10,000 mitochondria,
ion transport and trafficking within the endomembrane each of which contains 2–10 mtDNA copies, is likely to
system. The vinyl ether bond is more reduced relative to the counteract the effects of inactivating mutations in any one
acyl bond in a fatty acid, and thus, plasmalogens have been mtDNA (a phenomenon known as inter-mitochondrial com-
suggested to act as antioxidants, though this is controversial. plementation). In fact, recent high-throughput sequencing
In addition, DHA is a precursor of resolvins, docosatrienes analysis indicates that essentially all mitochondria are
and neuroprotections, which regulate inflammatory respon- heteroplasmic (containing both mutant and wild-type mtDNA
ses. Interestingly, plasmalogens are abundant in brain and genomes). On the other hand, replication of mtDNA occurs

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throughout the life of the cell with the potential for new Given the importance of mitochondrial function for
mutations arising. Thus, the composition of heteroplasmic neuronal health and the long life of neurons, there is an
mitochondria inherited at birth coupled with the generation especially great need in neurons for mitochondrial quality
of new mtDNA mutations over the course of time and with control (QC). In addition to the antioxidants described
genetic drift can all result in particular cells containing a above, mitochondrial quality control mechanisms include
large proportion of defective mitochondria genes (Keogh mitochondrial proteases, which degrade damaged proteins
and Chinnery 2015; Yang et al. 2015). (damaged, e.g., by oxidation) in the matrix and inter-
In summary, any dysfunction in OXPHOS affects membrane space; ubiquitin–proteasome systems that
mitochondrial function and can lead to excessive ROS remove damaged proteins located in the outer membrane or
production, which results in oxidative lipid, DNA and nuclear-coded mitochondrial proteins that are not correctly
protein damage. Living cells constantly generate ROS for imported; and vesicle-based removal of oxidated proteins/
physiological functions; however, excess ROS production lipids for targeting to lysosomes or peroxisomes. When
results in pathophysiological conditions such as ischemia– mitochondrial damage is too great, mitophagy, a form of
reperfusion injury, neurodegenerative diseases and aging autophagy, occurs, and if that is not sufficient to repair cell
(Balaban et al. 2005; West et al. 2011; Kotiadis et al. function, cells undergo apoptosis (Amadoro et al. 2014).
2014). Mitochondrial dynamics (transport along the cytoskele-
ton, regulation of mitochondrial architecture and connec-
tivity mediated by tethering, fusion and fission) also play a
Mitochondrial Function is Particularly Important role in mitochondrial QC. For instance, mitochondrial fis-
for Neuronal Function sion is required to fragment mitochondria into smaller pie-
ces as required for mitophagy. Hyperfusion occurs as a
Mitochondrial function has a pivotal role in neuronal health result of several different types of cellular stress, which is
for a number of reasons. One reason is that post-mitotic likely to facilitate inter-mitochondrial complementation and
neurons depend on mitochondrial metabolism exclusively (likely due to larger-sized mitochondria) protects cells
(in contrast to, e.g., replicating cells that use mostly gly- against mitophagy and apoptosis. Moreover, mitofusin2, a
colysis). They are also large and highly polarized cells with protein involved in mitochondrial fusion, is also important
many processes that have high demand for ATP con- for tethering mitochondria to the endoplasmic reticulum,
sumption. For instance, the function of synapses, which are and participates in the unfolded protein response (Shutt and
located at the tips of axons and dendrites that are often far McBride 2013; Zorzano and Claret 2015). Removing
from the cell body, requires a great deal of energy and the mitofusin2 from the mouse cerebellum leads to reduced
ability to buffer Ca2?, both of which are supplied by ETC activity, aberrant mitochondrial ultrastructure and
mitochondria. Thus, mitochondria are enriched in and have altered mitochondrial distribution, and result in degenera-
to be transported to (often distant) synapses (requiring even tion of Purkinje cells (Chen et al. 2007).
more energy for transport), and damaged mitochondria Mutations in genes encoding proteins, such as pink1,
have to be transported all the way back to the cell body in parkin, DJ-1 and a-synuclein in PD, amyloid beta (Ab) in
order to fuse with lysosomes during mitophagy (Amadoro AD, superoxide dismutase (SOD) in amyotrophic lateral
et al. 2014; Picone et al. 2014; Lin and Sheng 2015). sclerosis (ALS) and huntingtin in HD, not only disrupt
Consequently, mitochondrial impairment leads to necrosis mitochondrial membranes but also alter OXPHOS, thereby
and apoptosis of neurons (Green and Kroemer 2004; Nagley enhancing excessive ROS production (Reddy 2009; Guo
et al. 2010). Mitochondrial disorders have been categorized et al. 2013). These molecular aspects of neurodegenerative
into three general subclasses: (a) primary disorders due to disorders illuminate the fact that cellular organelles, espe-
mitochondrial gene mutations; (b) disorders relating to cially mitochondria and peroxisomes, play vital roles in the
nuclear gene mutations affecting mitochondrial function; and progression of these diseases.
(c) secondary disorders that result in the accumulation of For instance, PD is associated with loss of dopaminergic
mitochondrial damage over the time. Neurodegenerative neurons in the substantia nigra pars compacta. The result-
disorders typically belong to the latter category. Diseases ing loss of dopamine in the striatum causes the character-
based on mitochondrial dysfunction vary from well-known istic PD motor symptoms, which include tremor, rigidity,
diseases such as glaucoma, inflammation, neurodegenerative slowness in the execution of movement and postural
diseases, type 2 diabetes and cancers, to rare ones such as instability (Blesa et al. 2015; Hwang 2013; Exner et al.
Friedreich’s ataxia (FA), Kearns–Sayre syndrome (KSS) and 2012; Trempe and Fon 2013; Amadoro et al. 2014). On a
mitochondrial encephalopathy lactic acidosis and strokes cellular level, both sporadic and familial PD are strongly
(MELSAS) (Haas et al. 2008; Chaturvedi and Beal 2013). linked to oxidative stress, mitochondrial dysfunction (in

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particular inhibition of ETC complex I) and impaired N-methyl-D-aspartate (NMDA) receptors. High activity of
clearance of misfolded proteins and damaged organelles NMDA receptors triggers calcium influx into the cell,
(Exner et al. 2012; Han et al. 2014; Blesa et al. 2015). thereby resulting in neuronal death (Song et al. 2011).
Dopaminergic neurons appear to be particularly prone to Calcium clearing, in physiologic and pathological condi-
oxidative stress. Dopamine is itself a potential cause of tions, is undertaken by mitochondrial uptake, and mito-
oxidative stress as it is a target of MAO and can also auto- chondrial malfunction also abates calcium uptake and
oxidize, resulting in modification of a number of PD-re- mitochondrial membrane potential (Tillement et al. 2011).
lated proteins. Accordingly, there is evidence for oxidative Calcium overload in the cytosol induces ROS generation
stress in the substantia nigra of PD patients: oxidized lipids, via many signaling pathways, and this process could create
proteins and DNA are all found at increased levels, and a positive correlation between ROS and free calcium in
reduced glutathione is decreased (Hwang 2013). cells (Moreira et al. 2007). In contrast to necrosis, apop-
Accordingly, genes associated with familial PD have tosis is an active form of cell death, which can be induced
been implicated in the response to oxidative stress and to by ATP depletion in cells (Witte et al. 2010). Apoptotic
mitochondrial QC. These include the parkin gene, which pathways are integrated with the mitochondrion, due to its
encodes an E3 ubiquitin ligase, and the PINK1 gene, which central role in apoptosis (Rossignol and Frye 2012). Thus,
encodes a kinase (Exner et al. 2012; Tempe and Fon 2013; defective mitochondria can trigger neurodegenerative
Han et al. 2014). Parkin is recruited to defective mito- disorders.
chondria in a PINK1-dependent manner, resulting in Elevated ROS is correlated with several neurodegen-
mitophagy. In addition, both Parkin and PINK1 have been erative diseases. For example, it has been shown that
linked to mitochondrial fusion and fission. In particular, the mitochondrial complex I activity decreases in the sub-
mitochondrial fusion proteins mitofusin1 and mitofusin2 stantia nigra in PD, resulting in disrupted calcium home-
are ubiquitinated by Parkin, targeting them for destruction ostasis and elevated ROS generation (Legros et al. 2004;
by the proteasome, and are reduced in cells undergoing Eichner and Giguère 2011). Moreover, PD can be chem-
mitophagy. Parkin-induced inhibition of mitochondrial ically induced by inhibitors of complex I activity (1-
fusion may be important to allow fission, which is a pre- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),
requisite for mitophagy (Trempe and Fon 2013). Interest- paraquat and rotenone) (Schon et al. 2010). Rotenone,
ingly, Parkin is cysteine rich and therefore can be paraquat and MPTP elevate ROS generation, cytochrome c
inactivated by misfolding under conditions of oxidative release from mitochondria, and DNA damage in neurons
stress. Oxidatively modified, misfolded Parkin has been (Nicholls 2008). Similarly, low aerobic glucose utilization
found in the brains of PD patients (Exner et al. 2012; Blesa in basal ganglia and the cerebral cortex of Huntington’s
et al. 2015). disease (HD) patients (Herben-Dekker et al. 2014) leads to
In summary, neurodegenerative diseases are associated anaerobic metabolism with high lactate production. This
with oxidative stress and mitochondrial dysfunction. A phenomenon leads to enhancement in oxidative damage to
strategy of integrative therapies should be considered, neurons. In addition, complex II, III, IV deficiencies were
combining medical treatment with other therapies such as reported in HD patients’ postmortem brains (Lezi and
physical activities for patients with certain neurodegener- Swerdlow 2012). Mutant huntingtin protein (mHtt) also
ative diseases, especially therapies that lead to increased impairs the mitochondrial membrane potential and calcium
mitochondrial density or mitigation of mitochondrial homeostasis by influencing mitochondrial activities (Jin
functions. and Johnson 2010). Inhibition of complex II showed
similar behavioral and pathophysiological features to HD
Oxidative Stress and Neurodegeneration in rodents (Wallace and Fan 2009). In addition to energy
imbalance, calcium homeostasis and oxidant generation
Neurons have specific membrane potential features, which are also detected in AD patients’ tissues in correlation with
are required for neurotransmission and polarization. Na?- complex IV inhibition (Ferreiro et al. 2012). Taken toge-
K? ATPase plays a vital role in maintenance of neuronal ther, neurological disorders from ischemia to neurode-
membrane potential at resting state (Yu 2003). Therefore, generation have close correlation with mitochondrial
mitochondrial dysfunction or neuronal stressors such as activities. Hence, dysfunction in mitochondrial activities
ROS can disrupt polarization and maintenance of plasma can cause chronic damage and also trigger apoptotic or
membrane potential. When this occurs, cell can fall into a necrotic pathways in neurons and is a major pathogenic
rigid condition (Mochel and Haller 2011). Depolarization cause of neurodegenerative diseases (Obulesu and Lak-
of the cellular membrane leads to changes in the activity of shmi 2014).

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PGC1a in Organelle Biogenesis mice lacking PGC1a (McGill and Beal 2006). These mice
and Neuroprotection have neurodegenerative lesions in the striatum and are
hyperactive, which are hallmarks of HD in humans (Lin
Mitochondria et al. 2004; McGill and Beal 2006). Further studies showed
that PGC1a is required in 10T1/2 cells for induction of
Ligand-dependent nuclear receptor transcription factors have ROS-detoxifying enzymes such as copper/zinc superoxide
critical roles in many biological and cellular activities, dismutase (SOD1), manganese SOD (SOD2), catalase and
including mitochondrial metabolism. They respond to a vari- GPx in response to H2O2 treatment, that PGC1a null mice
ety of ligands and are controlled by many co-activators or co- are more sensitive to oxidative stress and that increasing
repressors (Evans 2005). Peroxisome proliferator-activated PGC1a can protect neural cells in culture from oxidative
receptor c co-activator a (PGC1a) was first identified as an stress-mediated death. These changes depend upon cAMP-
interactor of nuclear receptor transcription factor PPARc responsive element binding protein (CREB) as a potent
(Puigserver et al. 1998) and functions as a highly conserved PGC1a co-activator (St-Pierre et al. 2006; Wu et al. 2006).
transcriptional co-activator with important roles in mitochon- Other data indicate that mHtt can reduce PGC1a
drial oxidative metabolism, maintenance of glucose and lipid, expression by interfering with the CREB/transcription
and energy homeostasis (Corona and Duchen 2015; Villena initiation factor 4 (TAF4) complex (Cui et al. 2006). Cui
2015). PGC1a belongs to the PGC1 protein family and shares et al. 2006 showed a 30 % reduction of PGC1a mRNA in
high sequence similarity with its paralog, PGC1b (Lin et al. the caudate nucleus of striatum (the first region affected by
2002a). PGC1a regulates mitochondrial maintenance through HD) of presymptomatic HD patients, but not in cerebellum
expression of mitochondrial biogenesis factors (Kressler et al. or hippocampus. PGC1a reduction in HD abates mito-
2002; Wenz 2009). Nuclear respiratory factors 1 and 2 (NRF1 chondrial cytochrome c and cytochrome oxidase IV
and NRF2) (Wu et al. 1999), peroxisome proliferator receptor expression (Martin et al. 2011). In this regard, previous
alpha (PPARa) (Vega et al. 2000), estrogen-related receptor studies have shown that PGC1a overexpression has
alpha (ERRa) (Schreiber et al. 2004) and thyroid receptor (TR) potential to protect striatal neurons against expression of
(Zhang et al. 2004) are among the transcriptional factors polyglutamine expanded forms of huntingtin. In addition,
involved in mitochondria biogenesis that utilize PGC1a as a postmortem analysis of HD patient brains showed low
co-regulator. NRF1 and NRF2 are targets of PGC1a, and they expression levels of PGC1a target genes (Tsunemi et al.
regulate nuclear OXPHOS genes such as cytochrome c and 2012). In other types of neurodegenerative disorders such
mitochondrial transcription factor A (TFAM) (Kelly and as PD, PGC1a can act as a protective agent, as PGC1a-
Scarpulla 2004). Increases in PGC1a activity, which is induced deficient mice were more vulnerable to MPTP treatment.
by exercise, result in elevation of mitochondrial mass (Lin et al. Therefore, elevated PGC1a expression has a neuroprotec-
2002). Thus, PGC1a is the key regulator of mitochondrial tive property against MPTP toxicity (Mudò et al. 2012).
biogenesis (Scarpulla 2008; Kotiadis et al. 2014). Overall, it appears that PGC1a expression is neuroprotec-
tive in neurodegenerative diseases and aging.
Posttranslational modifications of PGC1a, such as
PGC1a and AD
deacetylation or phosphorylation, promote PGC1a activity
(Outeiro et al. 2008). Deacetylation of PGC1a by sirtuin-1
Alzheimer’s disease (AD) is a neurodegenerative disorder
(SIRT1) enhances PGC1a activity. This may be a key basis
characterized by neurofibrillary tangles (NFTs), which are
for the neuroprotective role of SIRT1 in AD, PD, HD and
generated by tau hyperphosphorylation and Ab deposition in
ALS (Qin et al. 2006; Zheng et al. 2010). Recent studies
the brain. AD has been correlation with PGC1a expression
have shown that parkin-interacting substrate (PARIS) is a
(Katsouri et al. 2011). Low expression of PGC1a in the brain
new partner protein in PD onset that has the potential to
of AD patients causes Ab formation because activity of the
repress PGC1a activity and enhance degeneration of
beta secretase (BACE1) enzyme, which generates Ab, is
dopaminergic neurons (Shin et al. 2011). In Alzheimer’s
regulated by PGC1a (Wang et al. 2013). In addition, mito-
disease, PGC1a expression is also abated (Sheng et al.
chondrial biogenesis and control of oxidative stress depend
2012) and its overexpression in animal models of AD
on PGC1a expression and any disruption in this condition
attenuated neurological phenotypes (Qin et al. 2009). In
causes neuronal death (Qin et al. 2009).
addition, ectopic expression of PGC1a decreased Ab
secretion and increased its soluble form (Katsouri et al.
PGC1a and HD 2011). This phenomenon indicated a link between quality
control of mitochondria and neurodegenerative disorders,
The first hints of a connection between PGC1a, impaired suggesting that amelioration in neurological disorders was
mitochondrial function and HD pathogenesis came from mediated by stimulating mitochondria biogenesis. In this

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regard, single-nucleotide polymorphisms (SNPs) have been oligomerization (Fujiwara et al. 2002; Sharon et al. 2003a).
detected in the gene encoding PGC1a in HD and PD Yakunin et al. (2010) also reported that mutations in PEX2,
individuals (Clark et al. 2011). Expression of SOD1 and PEX5 and PEX13 correlated with a-synuclein deposition in
SOD2, critical scavengers of ROS, are regulated by PGC1a neurons. Accumulation of a-synuclein is associated with
(Johnson et al. 2005; Weydt et al. 2009). This may account changes in metabolism of long-chain polyunsaturated fatty
for increased survival of SOD1 mutant ALS mice when acids (PUFAs), and postmortem brains of patients with PD
PGC1a was overexpressed. In this model, overexpression had high amounts of cytosolic PUFA (Sharon et al. 2003b).
of PGC1a increased antioxidant capacity by elevating Together, these findings suggest an impact on peroxisome
expression of other antioxidant enzymes, offsetting the loss function in PD. Moreover, an imbalance of metabolites
of SOD1 (Zhao et al. 2011). In accordance with these related to peroxisomal dysfunction might account for AD
observations, it has been reported that PGC1a silencing initiation (Nixon et al. 2000; Lin and Beal 2006), sug-
suppresses the expression of ROS-detoxifying enzymes gesting further the importance of optimal peroxisome
(Mudò et al. 2012). Based on these studies, enhancing the function in multiple neurodegenerative diseases. In this
PGC1a pathway might be a promising therapeutic strategy context, it is interesting to note that plasmalogens and
in neurological disorders (Handschin 2009; Wenz 2011). docosahexaenoicacid (DHA) (Calon et al. 2004) are among
the lipids that are synthesized in peroxisomes that have
Peroxisomes antioxidant features and may delay AD onset (Ginsberg
et al. 1995; Kalmijn et al. 1997). Plasmalogen synthesis is
Scavenger enzymes and proteins such as catalase, glu- increased by peroxisome proliferation, while DHA, a
tathione peroxidase, PMP20, peroxiredoxin 1 and epoxide polyunsaturated fatty acid, is synthesized in minute
hydrolase protect peroxisomes and the cell from H2O2 (van amounts by glial and endothelial peroxisomes in the final
der Valk et al. 1985). Oxidative stress induces morpho- step of b-oxidation from eicosapentaenoic acid or linolenic
logical changes in peroxisomes, which varies depending on acid (Conquer et al. 2000). Considering the fact that DHA
ROS levels (Lopez-Huertas et al. 2000). Over a threshold levels are decreased in AD patients’ brains and plasma on
level, ROS leads to peroxisome destruction, while below one hand, and disrupted production of very long chain fatty
this threshold, it induces elongation of peroxisomes, stim- acids in the neurons of the patients with AD on the other
ulates peroxisome proliferation and subsequently results in hand, this suggests that peroxisome proliferation can be
high density of peroxisomes with high antioxidant capacity targeted for therapeutic strategies in neurodegenerative
to decompose ROS (del Rı́o et al. 2002). In hippocampal disorders related to excessive ROS generation (Kou et al.
neurons, peroxisome proliferation protects neurons from 2011).
ROS and degeneration (Santos et al. 2005). Therefore, Taking into account the role of PGC1a in regulating
dysfunction of peroxisomes leads to accumulation of toxic mitochondrial and peroxisomal biogenesis, remodeling and
metabolites which predispose cells to aging and apoptosis proliferation (Koepke et al. 2007; Ivashchenko et al. 2011),
(Sheikh et al. 1998; Wood et al. 2006). the PGC1a pathway shows promise as a potential phar-
Peroxisome dysfunction causes neurological disruption, macological target to overcome neurological disorders
incomplete neuronal migration, dysmyelination, and associated with peroxisome and mitochondria dysfunction.
defects in neuronal development (Steinberg et al. 2006;
Kassmann et al. 2007). Disorders effecting peroxisome PGC1a/FNDC5/BDNF Pathway
function are subdivided into two groups: the peroxisome
biogenesis disorders (PBDs) and the peroxisomal enzyme Recently, there has been much interest, but also much
deficiencies (PEDs) (Wanders and Waterham 2006; Baes controversy, surrounding the discovery of irisin, a potential
and Aubourg 2009). PBDs are specified by the absence of myokine reported to elicit beneficial effects of exercise
functional peroxisomes due to deficiencies in the peroxi- (Boström et al. 2012).
somal transport system (Wanders and Waterham 2005). Fibronectin type III domain-containing 5 (FNDC5),
Mutations in peroxin (Pex) genes impact peroxisome bio- formerly known as peroxisomal protein (PeP), is a trans-
genesis and assembly, leading to PBDs (Baes and Van membrane precursor protein that is processed into a soluble
Veldhoven 2006). Biochemical outputs of these mutations secretory peptide termed ‘‘irisin’’ (Fig. 1), which is highly
are altered lipid metabolism, oxidative stress and mito- conserved among mammals. FNDC5 has an N-terminal
chondria dysfunction (Wanders and Waterham 2005). 29-amino acid signal peptide followed by a fibronectin
These types of changes are also associated with PD. a- domain that is flanked by a proteolytic cleavage site. After
Synuclein accumulation, an important hallmark of PD, cleavage of the signal peptide and the cleavage site
occurs due to alteration in posttranslational modifications flanking the fibronectin domain, the secreted irisin gly-
of a-synuclein such as phosphorylation, nitration and copeptide of 112 amino acids is produced. C-terminal to

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Fig. 1 Irisin is processed from

the irisin peptide region is a transmembrane domain and a increased irisin was a myokine responsible for browning of
cytoplasmic domain (Fig. 1) (Ferrer-Martı́nez et al. 2002; white adipose tissue through enhancing oxygen consump-
Ostadsharif et al. 2011; Lee et al. 2014). Spiegelmann’s tion and induction of expression of thermogenin (uncou-
group in 2012 reported that mouse transgenics with ele- pling protein 1) mRNA and other mitochondrial genes, as
vated PGC1a expression in muscle show ‘‘browning’’ of well as an increase in oxygen consumption induction
subcutaneous white adipose tissue. This occurs via a (Boström et al. 2012), and elevated levels of irisin in the
secreted factor, because conditioned media from myocytes blood were reported to help mice resist against insulin and
expressing PGC1a were also capable of inducing ‘‘brown- increased body weight. PGC1a regulates production of
ing’’ in primary subcutaneous adipocytes. They further irisin in muscles in cooperation with PPARa (Spiegelman
showed that PGC1a regulates FNDC5 expression and that 2013). The specific role of FNDC5/irisin in energy
FNDC5 is expressed in human muscle tissue in response to expenditure and differentiation of muscle and cardiac cells
exercise. Secretion of irisin also increases in response to has also been described (Aydin et al. 2014; Rabiee et al.
exercise in both mice and humans, and reducing irisin 2014).
levels in conditioned media from myocytes reduces their Exercise has also been shown to have beneficial effects
‘‘browning’’ effects on fat cell culture. Exogenous irisin on brain performance (Cotman et al. 2007; Mattson 2012),
expression in obese and insulin-resistant mice resulted in and has been reported to result in improved outcomes in

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Neuromol Med (2016) 18:1–15 9

Alzheimer’s disease and Parkinson’s disease (Ahlskog acting through tyrosine kinase receptor B (TrkB) (Binder
2011). Considering the brain’s dependence on glucose, it and Scharfman 2004). TrkB is abundant in the hippocam-
seemed plausible that PGC1a/FNDC5/irisin could also pus, amygdala and prefrontal cortex, where high expression
serve an essential role in mediating the effects of exercise of the BDNF is observed (Tapia-Arancibia et al. 2004).
on brain performance (Wrann et al. 2013). As described Activation of TrkB triggers various intracellular cascades
above, PGC1a has already been implicated in neurode- including mitogen-activated protein kinase (MAPK),
generation (Lin et al. 2004; Zheng et al. 2010; Castillo- phosphatidylinositol-3-kinase (PI3K) or phospholipase C-c
Quan 2011). Cerebellar purkinje cells in rat and mice also (PLCc) pathways (Huang and Reichardt 2001). The PI3K
express irisin (Dun et al. 2013). Furthermore, the results pathway has an important role in synaptic plasticity while
from our group showed that FNDC5 plays an important MAPK triggers differentiation and neurogenesis in the
role in neural specification of embryonic stem cells nervous system (Reichardt 2006). Impairment of synaptic
(Hashemi et al. 2013; Ghahrizjani et al. 2015). In this plasticity is a clinical feature of AD, HD and PD. The
regard, it has been shown that neurogenesis in the hip- numbers of synapses decline in AD, and their degeneration
pocampus is regulated by irisin, and increased numbers of has a close correlation with disease progression (Selkoe
mouse hippocampal neurons are produced in the presence and Schenk 2003). Loss of synapses leads to impairment in
of irisin (Moon et al. 2013). Our work also indicated that hippocampal memory (Chapman et al. 1999). In HD, mHtt
overexpression of FNDC5 could enhance the overall rate of aggregation causes synaptic degeneration in the striatum
neural differentiation of embryonic stem cells (Forouzanfar and worsening of cognitive performance (Milnerwood and
et al. 2015). In 2013, Wrann et al. (2013) reported that Raymond 2010). In addition, loss of motor and cognitive
FNDC5 expression was induced in the hippocampus by functions in PD patients has a correlation with synaptic
exercising through the FNDC5/PGC1a/BDNF pathway. decline in the striatum (Picconi et al. 2012). In the patients’
Hippocampal neurons have a critical role in AD. Thus, brains of these neurodegenerative disorders, BDNF levels
these findings suggest that FNDC5 could serve as a neu- and its transcripts are significantly reduced (Tapia-Aran-
rogenic factor in the hippocampus and delay AD onset as cibia et al. 2008). Incidentally, in stroke BDNF secretion is
well as other neurodegenerative disorders through exercise, altered, and elevation of BDNF was detected in epilepsy
so further studies are needed to validate links between and autism (Connolly et al. 2006; Tsai 2006). The presence
exercise and irisin, before we consider its potential benefit of the TrkB in cortical neurons decreases in AD, and this
to AD. phenomenon suppresses the effectiveness of BDNF (Tong
Brain-derived neurotrophic factor (BDNF) is known to et al. 2004). On the other hand, recent studies have shown
promote brain development (Greenberg et al. 2009). BDNF that BDNF treatment protected striatal neurons against
also appears to be a critical mediator of the benefits of neurotoxin, 6-hydroxy dopamine [6-OHDA and MPTP in
exercise on brain function, since exercise induces its PD models (Sun et al. 2005)]. A neuroprotective feature of
expression in a number of brain regions, including the BDNF in neurodegenerative disorders includes Bcl2/Bax
hippocampus (Cotman et al. 2007), which is an important regulation. BDNF acts as an anti-apoptotic protein by up-
site for memory and learning in the brain (Petzold et al. regulating activity of the anti-apoptotic protein Bcl2, while
2015). decreasing the pro-apoptotic Bax protein, both of which act
How FNDC5 influences neuronal health and the bene- at mitochondria (Schäbitz et al. 2000).
ficial effects of exercise remains to be elucidated. How- In addition to the neuroprotective roles associated with
ever, recent findings indicate that irisin triggers expression BDNF levels, SNPs in the coding sequence of its gene are
of BDNF (Wrann et al. 2013). The neuroprotective effects correlated with neurological disorders. A Val to Met resi-
of BDNF through physical activity have been established due substitution at position 66 in the BDNF gene leads to
(Mattson 2012; Phillips et al. 2014). BDNF, along with the vulnerability of neurons to disorders such as Alzheimer’s
other neurotrophins (NGF, neurotrophin-3, neurotrophin-4/ disease (Ventriglia et al. 2002), depression (Sen et al. 2003)
5, neurotrophin-6 and neurotrophin-7), exerts its action and PD (Momose et al. 2002). In addition to SNPs in
through binding to tyrosine kinase receptors (Fiore et al. BDNF, considering the fact that BDNF is produced as a
2009). BDNF is expressed in the central and peripheral precursor protein, SNPs related to trafficking and secretion
nervous system during fetal and postnatal development, of BDNF in neurons (Chen et al. 2004) leads to cognitive
and plays an important role in serotonergic, dopaminer- impairments due to synaptic degeneration (Desai et al.
gic, noradrenergic and cholinergic neuronal specification 1999). As mentioned above, one of the pathways down-
(Dwivedi 2009). In addition, BDNF influences synaptic stream of BDNF/TrkB is MAPK, which in turn phospho-
plasticity by intensification of long-term potentiation (LTP) rylates CREB as its target (Pizzorusso et al. 2000).
(McAllister 2001). One of the protective mechanisms of Phosphorylated CREB is a transcription factor and exerts
neurons against toxicity is enhanced expression of BDNF, important roles in neuroprotection, neurotransmission and

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learning and memory (Carlezon et al. 2005). CREB also activities involving PGC1 and BDNF that center around
controls PGC1a expression (Volakakis et al. 2010). Such a neuronal health and the positive impact that exercise plays
positive feedback has been reported in the neocortex and on aging-related pathologies. Moreover, our group recently
striatum (Giampà et al. 2013). This appears to be the showed that FNDC5 promotes neural development and
molecular mechanism underlying improvement of neuro- differentiation of embryonic stem cells (Hashemi et al.
logical disorders following exercise in depression, epi- 2013), a perhaps separate role from the controversial one
lepsy, stroke and Alzheimer’s disease (Kobilo et al. 2011). proposed for irisin in neuronal metabolic health. Also,
Irisin was discovered 3 years ago as a factor that is numerous studies have shown that exercise protects the
induced by exercise and converts white adipose tissue to brain against neurodegeneration and the progression and
brown adipose in mice (Boström et al. 2012). However, onset of neurological disorders such as AD and PD. Since
concern over the accurate detection of irisin peptide arose PGC1a/FNDC5/BDNF was discerned as a critical pathway
immediately (Erickson 2013), and a recent report chal- in neuroprotection elicited by exercise, irisin could serve as
lenges the conservation of the physiological effects of irisin a protective factor by its activation of BDNF expression.
in humans (Albrecht et al. 2015). Recent studies showed Based on previous reports, BDNF is secreted from neurons
that the start codon in human FNDC5 is a non-canonical and initiates many intracellular signaling events through
AUA codon (Erickson 2013; Raschke et al. 2013), which TrkB receptors. These pathways have positive feedback on
occurs at a low frequency in the human genome and is less CREB activities and lead to enhancement in PGC1a
efficient at translation (Ivanov et al. 2011). The result is a expression. The net result is improvement in brain per-
much lower level of expression of FNDC5 in humans formance. Further evaluation will establish whether the
compared to mice (Raschke et al. 2013). Moreover, the first PGC1a/FNDC5/BDNF pathway will be an effective target
ATG codon in human FNDC5 is located 76 codons 30 to for therapeutic interventions in neurological diseases and
this start codon and, if utilized, generates a frameshift and aging. If the promise of irisin holds, it has the therapeutic
premature truncation that would preclude synthesis of irisin potential to ameliorate the effects of aging and CNS
(Raschke et al. 2013). In addition, they showed that disorders.
recombinant irisin could not differentiate preadipocyte to
browning fat (Raschke et al. 2013). Moreover, the antibody Acknowledgments We thank all of our colleagues at the Royan
Institute for Biotechnology who contributed to the work discussed in
previously used for irisin detection was specific to the C this review.
terminus of FNDC5, which is not present in the cleaved
and secreted irisin (Erickson 2013). In a more recent report,
it was revealed that the commonly used commercial ELISA References
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