The Scientist : The Genes of Parkinsons Disease 2/22/11 12:25 PM

The Scientist

Volume 25 | Issue 2 | Page 36

By Bobby Thomas and M. Flint Beal

The Genes of Parkinson’s Disease

The minority of Parkinson’s cases now known to
have genetic origins are shedding light on the
cellular mechanisms of all the rest, bringing
researchers closer to a cause—and perhaps a cure.

It took centuries for the slumped

posture, trembling hands, poor
balance, and cognitive
impairments that characterize
Parkinson’s disease (PD) to be
recognized as manifestations of a
single illness, distinct from other
maladies of old age. It was a feat
of methodical observation. But
while the pace of scientific
research has accelerated greatly,
especially in recent years, it may
still be many years before we
understand what causes the
disease.

In the last two centuries,

researchers have shown that PD
results from the relentless
degeneration of specific neuronal
populations in the substantia
Gerald Slota nigra, most notably those that
produce dopamine, causing a
deficiency that leads to motor abnormalities. The condition is usually partially
treatable (mainly with dopamine-replacement therapy) for a few years after
diagnosis. But this is generally followed by years of decline for which there is no
effective therapy, culminating in premature death. Today, after Alzheimer’s
disease, PD is the second most common neurodegenerative disorder, affecting
more than 6 million people worldwide.

For most of the twentieth century, genetic

predisposition was thought to play a negligible
role in the disease. The strongest evidence was
epidemiological and seemed to point to
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While a hereditary cause can still only be linked to

about 5 percent of Parkinson’s cases, these genes are starting to shed light on
the universal processes that might cause dopaminergic neurons to die. By probing
these genes, a new story is beginning to emerge—one that suggests
environmental factors may exacerbate disease in individuals who are susceptible,
because genetic factors curtail their ability to cope with toxic damage. Indeed,
many of the genes mutated in hereditary Parkinson’s disease play a pathogenic
role in mitochondria as well as in the ubiquitin proteasome system and the
autophagy-lysosome machinery, both of which remove misfolded proteins and
damaged organelles. However, some of the implicated proteins have functions
that do not necessarily fit into these scenarios, so more work is needed to
understand whether and how the various disease-associated genes interact.
Recent studies have identified Parkinson’s-related genes containing either gain-
of-function mutations (those that generate a gene product with a novel function)
or loss-of-function mutations (those that render the gene product
nonfunctional). These genes demonstrate that we are getting closer to
understanding the mechanisms of neuronal damage in Parkinson’s disease.

Gain-of-function mutations

The α-synuclein gene mutation. The first big breakthrough came in 1997 when
researchers were studying several families with the inherited dominant form of
Parkinson’s disease—a form that required a toxic gain-of-function mutation in
the α-synuclein gene locus (reviewed in reference 1). Later, α-synuclein was

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The Scientist : The Genes of Parkinsons Disease 2/22/11 12:25 PM

identified as a major component of Lewy bodies, the fibrous bundles within

neurons seen in autopsied brains of Parkinson’s patients. Normally, the α-
synuclein protein regulates the release of neurotransmitters; however, mutations
to the α-synuclein gene, SNCA—both point mutations and multiplications—
occurred in these familial cases of Parkinson’s disease, pointing to a role for this
gene in PD. The finding also suggested that individuals with no mutations, but
who simply produced a higher than average level of α-synuclein, had a greater
risk of developing PD than those with a lower α-synuclein levels. 2

Both pathogenic mutations in the

gene and elevated concentrations
of the protein will give α-
synuclein a propensity to develop
a β-sheet structure. These
structures readily polymerize into
oligomers and higher-order
aggregates, such as the fibrils
that are characteristic of Lewy
bodies. 1 Not only do genetic
alterations instigate disease, but
α-synuclein aggregation is also
worsened by various types of
post-translational modifications
to the normal protein, 3
potentially expanding the number
of factors involved in propagating A colored transmission electron micrograph (TEM) of a
Parkinson’s. neuronal section containing a Lewy body made up of α-
synuclein filaments in pink and blue.
Parkinson’s researchers began to
look beyond the genes that code Lysia Forno / Photo Researchers, Inc.

for α-synuclein. For example,

when investigators inhibited mitochondrial complex I—a protein critical to the
mitochondrial electron transport that powers the cell—α-synuclein began to form
aggregates and became toxic to the cell. The results suggested that disrupted
mitochondria might themselves spur α-synuclein bundle formation and, in
theory, also cause Parkinson’s disease. 4

Curiously, however, researchers also found evidence that α-synuclein

overexpression induces mitochondrial dysfunction, resulting in electron leakage
that causes oxidative stress in the cell, ultimately leading to cell death. 5 It’s
unclear whether the chicken comes before the egg or vice versa: is it the
overabundance of α-synuclein that damages the mitochondria, or is it a damaged
mitochondrial electron pump mechanism that initiates the process that leads to
α-synuclein bundling? There appears to be evidence for both possibilities.

With α-synuclein a proven player,

It wasn’t until 1997 that
researchers started working on explaining
researchers started to how the mutations that either changed
the shape of the protein or increased its
consider the genetics of expression might cause neuronal death.
Parkinson’s disease. These investigations have yielded no
shortage of hypotheses. Some studies
suggest that α-synuclein oligomers bound
together in a doughnut shape might form pores in the plasma membrane,
allowing calcium ions to accumulate in the cell at toxic levels. 6 (The idea isn’t
so far-fetched, considering that α-synuclein monomers alone readily associate
with the plasma membrane.) Yet others suggest that an overabundance of α-
synuclein tends to gunk up a neuron’s ability to release and recycle
neurotransmitters that are stored in the vesicles of firing neurons. 7 (See graphic
below.) The thinking is that the buildup of this protein interferes with synaptic
transmission by preventing docked vesicles at the presynaptic membrane from
releasing into the synaptic space. This reduces the overall dopamine being
transmitted by these neurons, thereby increasing intracellular dopamine to toxic
levels and permanently damaging the dopamine-producing cells. 8

Finally, some research suggests that it is not an overabundance of α-synuclein,

but rather the mutant forms of the protein that cause damage by throwing
several monkey wrenches into the cell’s ability to get rid of all misfolded
proteins. Mutant species of α-synuclein are poor substrates for degradation by
the proteasome, the cell’s recycling complex; they inhibit the digestion of
proteins by proteolysis; they block lysosomes, which fuse with other vesicles to
break up their contents as well as blocking the vesicles that are tagged with
chaperone proteins for fusion with lysosomes during autophagy 8 ; and they
disrupt ER-Golgi trafficking, which is vital to vesicle transport and a number of
secretory pathways.

Are all of these mechanisms triggered when α-synuclein becomes abundant or

mutated in the cell? Is there a hierarchy—one mechanism that predominates over
the others? Would we need to disable all of them in order to prevent or slow
disease in susceptible individuals? These are still the big questions that require
further testing, but whatever the exact mechanism(s) involved, it is clear that α-
synuclein aggregates exert toxic effects on several important cellular functions
necessary for the survival of dopaminergic neurons.

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The Scientist : The Genes of Parkinsons Disease 2/22/11 12:25 PM

The LRRK2 gene mutation. A second autosomal dominant Parkinson’s gene

involving a toxic gain-of-function mutation was discovered in 2004 and named
LRRK2 (leucine-rich repeat kinase 2). Mutations in this gene are found in about 5-
6 percent of all familial cases as well as 2 percent of cases with no known cause.
Interestingly, this mutation can cause early-onset Parkinson’s in families from
diverse ethnic backgrounds, 1 in a form that is identical in clinical symptoms to
late-onset Parkinson’s. LRRK2 encodes a protein that is part of a larger
multidomain protein with characteristic GTPase and kinase domains. While a
great deal of effort has gone into identifying the protein’s normal physiological
functions in the cell, only a few of its substrates—which appear to promote
neuron growth by activating protein translation or cytoskeletal reorganization—
have so far been tentatively identified. Most of LRRK2’s substrates, its binding
partners and its regulators have yet to be confirmed or clarified, and
consequently its role in disease is still a mystery.

Many of the LRRK2 transgenic mouse models of PD develop cardinal abnormalities

of the disease, such as stimulated dopamine neurotransmission or behavioral
deficits, and progressive age-dependent motor deficits leading to immobility
that are responsive to the dopaminergic drugs L-DOPA and apomorphine. 9
Strikingly, there is an additive effect when both LRRK2 and the α-synuclein gene
are mutated in mice, whereas a deficiency of LRRK2 limits the toxic effects of
mutant α-synuclein, suggesting that the two proteins are involved in common
disease development pathways.

Recently, investigators were able to determine that in vivo, mutated LRRK2

exerted toxicity resulting from its enhanced kinase activity. Overexpression of
normal LRRK2 or a “kinase-dead” version of the enzyme did not produce these ill
effects. What’s more, the mutant-LRRK2-mediated neurotoxicity was blocked by
selective LRRK2 kinase inhibitors, suggesting that the latter could become a new
treatment for PD. 10

GENE LOCI IDENTIFIED FOR PARKINSON’S DISEASE AND THEIR

PROBABLE FUNCTIONS
Locus Gene Chromosome Inheritance Probable function
PARK1 α- Presynaptic protein, Lewy body,
4q21 Dominant
and 4 synuclein lipid and vesicle dynamics
PARK2 Parkin 6q25.2-27 Recessive Ubiquitin E3 ligase, mitophagy
PARK3 Unknown 2p13 Dominant Unknown
PARK5 UCH-L1 4p14 Dominant Ubiquitin C-terminal hydrolase
PARK6 PINK1 1p35-36 Recessive Mitochondrial kinase
PARK7 DJ-1 1p36 Recessive Oxidative stress
Kinase signaling, cytoskeletal
PARK8 LRRK2 12p11.2 Dominant
dynamics, protein translation
PARK9 ATP13A2 1p36 Recessive Unknown
PARK10 Unknown 1p32 Dominant Unknown
PARK11 GIGYF2 2p37 Dominant IGF-1 signaling
PARK12 Unknown Xq21-q25 X-linked Unknown
PARK13 Omi/Htra2 2p13 Unknown Mitochondrial serine protease
PARK14 PLA2G6 22q13 Recessive Phospholipase enzyme
PARK15 FBXO7 22q11 Recessive Ubiquitin E3 ligase
PARK16 Unknown 1q32 Unknown Unknown
Source: Human Mol Genet, 16:R183-94,2007

Click for larger image

Lucy Reading-Ikkanda

Loss-of-function mutations

There is compelling evidence suggesting that loss-of-function mutations

rendering the three genes, parkin, PINK1 and DJ-1, functionally inactive,
underlie common forms of autosomal-recessive PD. Patients with loss-of-function
parkin (also known as PARK2) mutations account for an estimated 40-50 percent
of all familial early-onset cases of PD, whereas mutations in PINK1 (PARK6 ) and

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The Scientist : The Genes of Parkinsons Disease 2/22/11 12:25 PM

DJ-1 (PARK7 ) are less common. 1 Several studies have demonstrated that
products of all three recessive genes preserve mitochondrial functions, protect
against reactive oxygen species, or play a role in protein degradation pathways.
Normally, parkin tags proteins with ubiquitin, a protein that acts as an address
label targeting tagged proteins either for destruction via the proteasome, or for
other signaling pathways such as DNA repair, endocytosis, transcriptional
regulation, and protein trafficking. 1 Mutations in the parkin gene lead to a loss
of this tagging ability. Although a number of the proteins that parkin tags for
degradation have been identified, no consensus has emerged on which of these
may (if not tagged) accumulate in the cell, leading to neurodegeneration in PD.

Recent studies point towards both the parkin and PINK1 proteins playing a
prominent role in preserving mitochondrial functions. Mutant flies that lack
parkin or PINK1 genes exhibit abnormal mitochondria, as well as enhanced
sensitivity to oxidative stress, muscle degeneration, and significant loss of
dopamine-producing neurons. Mice lacking parkin and PINK1 also exhibit
mitochondrial dysfunction that results in heightened oxidative stress.

Interestingly, researchers were able to rescue mitochondrial dysfunctions in flies

lacking PINK1 by increasing parkin expression. On the other hand, increasing
expression of PINK1 had no effect on dysfunctions in flies lacking parkin. 1 This
neatly puts parkin and PINK1 in a common pathway, with PINK1 functioning
upstream from parkin. Several recent studies also found parkin and PINK1
involvement in facilitating autophagic clearance of damaged mitochondria, by a
process known as mitophagy. 11 In cellular models, parkin is selectively targeted
to impaired mitochondria, a process that relies on the expression of PINK1
through phosphorylation of parkin. 11 These data suggest that a failure to
activate efficient mitophagy may serve as an important pathogenic mechanism
of cell death in PD.

The third recessive gene, DJ-1, produces a molecular chaperone that aids in
protein folding, in addition to other functions. It is found in the cytosol, the
mitochondrial matrix, and mitochondrial intermembrane space. In cellular
models, it regulates redox-dependent signaling pathways and acts as a regulator
of antioxidant gene expression, while gene deletion studies show that it counters
oxidative stress in mitochondria. Recent studies indicate that DJ-1 deficiency is
associated with perturbed mitochondrial dynamics and autophagic
dysregulation, 12 linking its functions with those mediated by parkin and PINK1.
Despite all these advances, we still lack a clear picture of how exactly these
three proteins (parkin, PINK1, and DJ-1) fit in a common pathway for disease
development.

Future focus

The identification and characterization of familial PD-linked genes has sparked

an extremely fruitful line of research, delineating molecular pathways that are
involved in the pathogenesis of PD. Recent evidence suggests that these
molecular pathways are not only relevant to the rare familial variants of PD, but
also to the more common noninherited version of the disease. Genome-wide
association studies are also contributing by providing a new tool for searching out
other PD-associated genes. So far, the proteins that have been linked to PD by
genetic studies have roles in lipid and vesicle dynamics (α-synuclein), the
ubiquitin-proteasome system (parkin), abnormal kinase function (LRRK2),
oxidative stress, and mitochondrial dysfunction (DJ-1, PINK1, parkin). It appears
as though these disparate functions must converge, leading to the dysfunction
and death of dopaminergic neurons.

While we have made great strides in understanding all these functions, the
connections between them are not immediately apparent. Therefore, the major
focus of future research should be to identify common underlying mechanisms by
which familial PD-linked genes impact the survival of dopaminergic neurons—
mechanisms which will offer new and tractable targets for developing drugs to
prevent and treat PD.

F1000 Members Bobby Thomas and M. Flint Beal are at Weill Cornell Medical
School in New York City.

This article is adapted from an upcoming review in F1000 Medicine

Reports. It will be available for citation at f1000.com/reports
(open access)

References:
1. B. Thomas, M.F. Beal, “Parkinson’s disease,” Hum Mol Genet, 16:R183-94,
2007.
2. S. Winkler et al., “α-Synuclein and Parkinson disease susceptibility,”
Neurology, 69:1745-50, 2007.
3. A. Oueslati et al., “Role of post-translational modifications in modulating the
structure, function and toxicity of α-synuclein: Implications for Parkinson’s
disease pathogenesis and therapies,” Prog Brain Res, 183:115-45, 2010.
4. R. Banerjee et al., “Mitochondrial dysfunction in the limelight of Parkinson’s
disease pathogenesis,” Biochim Biophys Acta, 1792:651-63, 2009.
5. L.J. Hsu et al., “α-Synuclein promotes mitochondrial deficit and oxidative
stress,” Am J Pathol, 157:401-10, 2000.

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6. K. Furukawa et al., “Plasma membrane ion permeability induced by mutant α-

synuclein contributes to the degeneration of neural cells,” J Neurochem, 97:1071-
77, 2006.
7. V.M. Nemani et al., “Increased expression of alpha-synuclein reduces neuro-
transmitter release by inhibiting synaptic vesicle reclustering after endocytosis,”
Neuron, 65:66-79, 2010. Free F1000 Evaluation
8. A.A. Cooper et al., “α-Synuclein blocks ER-Golgi traffic and Rab1 rescues
neuron loss in Parkinson’s models,” Science, 313:324-28, 2006.
9. T.M. Dawson et al., “Genetic animal models of Parkinson’s disease,” Neuron,
66:646-61, 2010.
10. B.D. Lee et al., “Inhibitors of leucine-rich repeat kinase-2 protect against
models of Parkinson’s disease,” Nat Med, 16:998-1000, 2010. Free F1000
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11. R. Banerjee et al., “Autophagy in neurodegenerative disorders: pathogenic
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12. I. Irrcher et al., “Loss of the Parkinson’s disease-linked gene DJ-1 perturbs
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