Running head: PATHOGENIC PARK2 GENE ABERRATIONS 1

Pathogenic Implications of PARK2 Gene Aberrations

Tamara McKlveen
South University









PATHOGENIC PARK2 GENE ABERRATIONS 2

Abstract
Scientific research in the field of genetics has become increasingly significant over the past
several decades, with many advances being made in the discovery of genetically-based
pathogens. Researchers are now able to identify and trace the causes of many these diseases,
opening the doorway to a better understanding of these disorders which, one would hope, could
eventually lead to a better understanding of how to treat and even cure some of these disorders.
This paper will explore genetic pathogens related to the human gene identified as PARK2.
Originally discovered in 1994, PARK2 aberrations were noted to be related to an early onset
form of Parkinson disease (Yamamura, 2010). However, continued studies have linked
numerous disorders to PARK2, including high blood pressure, diabetes mellitus, certain cancers,
increased susceptibility to leprosy and carbon monoxide poisoning, attention-
deficit/hyperactivity disorder (ADHD) and, most recently, autism spectrum disorders (ASD).
The early onset form of Parkinson disease is an autosomal recessive trait, meaning that in order
for disease to be expressed a person must inherit the PARK2 aberrations from both parents
(Spratt, Martinez-Torres, Noh, Mercier, Manczyk, Barber, Shaw, 2013). The implications
here are interesting; with the increased availability of genetic testing and counseling it is possible
that one day we will be able to remove heritable genetic aberrations from family lines
completely.




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Pathogenic Implications of PARK2 Gene Aberrations
Recently, the writer of this article had an up-close and personal encounter with human
genetics, specifically the PARK2 gene. This writers son, Joshua, has been diagnosed with ASD
since he was seventeen months old. For the past two years Joshua has been seeing a neurologist
for medication management to aid in sleep problems. A few months ago the neurologist
suggested that Joshua should have genetic testing. When the test results came back, a nurse
called this writers home to inform her that the test results came back abnormal. However, the
nurse was unable to relay exactly how the results were abnormal or what an abnormal result
meant. In fact, the nurse was unable to answer any questions at all about the findings and even
informed this writer that there was no point in making a follow up visit with the neurologist
because he wouldnt be able to explain things any better. However, she did suggest that it would
be very important for the rest of the family to now be tested. She couldnt explain why that
should be done either. The nurse did finally and grudgingly agree to send a copy of the findings
in the mail, which arrived more than a week later.
Upon reviewing the report, this writer was surprised to find a very clear description of the
problem. Joshua has a microdeletion of part of a gene known as PARK2. Upon completing a
quick Internet search, this writer was shocked to learn that the PARK2 gene is related to juvenile
onset Parkinsons disease. Panic ensued; having limited knowledge of genetics, this writer
assumed that in addition to autism spectrum disorder, Joshua now had Parkinsons disease to
look forward to. This is the danger of unqualified medical personal delivering poor information.
Upon further research, this writer discovered that there were in fact many cases of autism related
to copy number variations and deletions in the PARK2 gene. In other words, the whole dramatic
episode proved what was already known; Joshua has autism spectrum disorder. The research
PATHOGENIC PARK2 GENE ABERRATIONS 4

showed had other surprising finds too; in fact, many disorders were linked to aberration on
PARK2. Having a post positivist world view, this researcher knew she wanted to find out
everything there was to know about the PARK2 gene; how it was effecting Joshua, how it might
be effecting other members of the family, and how it might one day impact her grandchildren.
Chromosomes are comprised of two sections, or arms joined in the center by a
centromere (US National Library of Medicine, 2014). One arm, labeled the p arm, is generally
shorter than the other arm, labeled the q arm. There are 23 pairs of human chromosomes. To
describe where a specific gene lies, one first identifies the chromosome in question, whether the
gene is on the p or q arm, and then a numeric location indicating how far from the centromere the
gene is located. The PARK2 gene is on the q, or long, arm of chromosome 6 between locations
25.2 and 27. Thus, to describe PARK2 we would say 6q25.2-27. PARK2 is indicated by the
yellow arrow in the following diagram:

PARK2 is on the terminal end of the q arm, terminal meaning far from the centromere
(US National Library of Medicine, 2014). PARK2 is identified as one of the largest genes,
comprised of base pairs 161,768,589 through 163,148,883. Base pairs are complementary
molecules held together by weak chemical bonds, forming the double helix shape of human
Centromere
Terminus
p arm
q arm
PARK2
PATHOGENIC PARK2 GENE ABERRATIONS 5

DNA. If one describes DNA as a sort of twisted ladder shape, it is the base pairs that form the
rungs of the ladder.

There are four chemical bases in DNA: thymine, adenine, cytosine, and guanine (US
National Library of Medicine, 2014). It is important to understand that these bases usually like
to bond in a certain way; thymine usually bonds with adenine and cytosine usually bonds with
guanine. When this does not happen, say for instance a bone occurs between thymine and
cytosine, the resulting error is known as a Single Nucleotide Polymorphism, or SNP (pronounced
snip). Most humans have hundreds of SNPs, but understanding of SNPs is limited. They are
currently not considered significant unless they occur in groupings. However, researchers have
discovered many SNPs that do result in disease processes; the significance of disease generating
SNPs will be discussed in greater detail in the literature review section.
There are many other kinds of chromosomal aberrations that are related to phenotypic
abnormalities. Two that will be discussed in this research are chromosomal inversions and copy
number variations. Inversion occurs when the end of a chromosome breaks of, inverts itself end
to end, and reattaches at the breakage site (US National Library of Medicine, 2014). Inversions
PATHOGENIC PARK2 GENE ABERRATIONS 6

do not always cause problems, although they can. Copy number variations are when the number
of genes on a chromosome varies between individuals; most genes occur in the same number and
in the same order in all humans. Copy number variations occur when a gene shows up more than
once on a chromosome, or when the gene is deleted.
The PARK2 gene, being both large in comparison to other identified genes and located on
the terminal end of chromosome 6, tends to be an area where frequent genetic abnormalities are
found. In fact, location 6q26 is also known as FRA6E, the third most fragile chromosomal site
(Lee, Cho, & Hallford, 2011). This paper will provide an overview of different known
aberrations that occur in PARK2 as well as their phenotypic significance. Following, proposed
areas of further research will be discussed.
Literature Review
PARK2 and Early Onset Parkinson Disease
As noted above, the PARK2 gene was originally discovered during work on familial
heredity studies of early onset Parkinson disease (Yamamura, 2010). Since its discovery in
1994, other genes have been found to be related to early onset Parkinson disease, but PARK2
remains the most important (Kim, Seong, Jeon, Kim, Ko, Kim, & Park, 2012). Frequently,
PARK2 aberrations related to early onset Parkinson disease occur as exon rearrangements and
deletions. Exons are portions of the gene that code for amino acids (US National Library of
Medicine, 2014). In 2012, Kim et al. found that patients with apparent contiguous multiexon
deletions might actually be compound heterozygous for two different adjacent exon deletions.
What is clear is that mutations in PARK2 lead to decreased levels of an important
ubiquitin-protein ligase known as Parkin (Spratt, et al., 2013). Parkins job is to seek out
PATHOGENIC PARK2 GENE ABERRATIONS 7

damaged proteins and macrophage cells and destroy them. This helps to regulate availability of
protein (energy) for cell activity. When Parkin is unable to do this effectively, the result is an
excess of damaged proteins. This appears to lead to neuronal loss and gliosis in the part
compacts of the substantia nigra and in the locus coeruleus, leading to early onset Parkinson
disease. Spratt et al. also note that more than 50% of autosomal recessive juvenile Parkinsonian
cases are caused by this dysfunction.
PARK2 and Diabetes Mellitus
Recent studies in diabetes mellitus have discovered that impaired insulin regulation in the
brain may be linked to neurodegenerative diseases such as Parkinson disease (Jin, Kim, Lee,
Kim, Go, Lee, Jeong, 2014). This prompted researchers to wonder whether or not there is a
link between diabetes and Parkinson disease. Progressive -cell failure is the central component
of the onset of diabetes mellitus. Defects in mitochondrial function in -cells are closely related
to both the production of insulin and glucose-stimulated insulin secretion. Recall that PARK2 is
thought to be related to mitochondrial dysfunction and quality control; PARK2 generates Parkin,
which is an ubiquitin-protein ligase; its function is to attach to damaged cells to mark them for
destruction. Researchers began to wonder if there was a link between the mitochondrial
dysfunction seen in the -cells and the mitochondrial dysfunction that accounted for the early
onset form of Parkinson disease.
Three independent studies on Mexican-Americans and Pima Indians have indicated a link
between PARK2 and diabetes mellitus (Jin, et al., 2014). Researchers attempted to duplicate
these findings in the Korean population. They found two SNPs that reached statistical
significance; these were identified as rs10455889 and rs9365294. According to the NCBI Map
PATHOGENIC PARK2 GENE ABERRATIONS 8

Viewer, these SNPs would correspond to base pairs 6:161,913,437 and 6:161,913,663, both of
which fall within PARK2 (National Center for Biotechnology Information, 2014). However,
results were significant for men only and were not replicated in three subsequent studies (Jin, et
al., 2014). Researchers suggested that these differences may be accounted for in the nature of
the populations. Diabetes mellitus does have several gender-specific associations that may
account for why the SNPs were only significant in Korean males. Researchers also theorized
that since the subsequent studies were performed in different ethnic populations, genetic distance
and subject size may account for the failure of the findings to be replicated in subsequent studies.
It should be noted, however, that two additional SNPs in PARK2 were recently identified
in the NHLBI Family Heart Study as being associated with insulin in the database of genotypes
and phenotypes (Jin, et al., 2014). These are 6:161,914,659 and 6:161,923,155. Jin, et al.
summarized their findings by proposing that impaired mitochondrial quality control caused by
decreased regulation of PARK2 contributes to -cell dysfunction in the same way that neuronal
dysfunction is caused by impaired mitochondrial quality control in Parkinson disease.
PARK2 and High Blood Pressure
Genetic variations in the PARK2 gene are significantly associated with high blood
pressure in both Nigerian and Korean populations (Jin, Hong, Kim, Kim, Yoo, Oh, & Jeong,
2011). In studying the PARK2 gene, researchers discovered statistical significance in the
reoccurrence of two SNPs; one located at 6:162848929 and one located at 6:162300908.
However, subsequent testing failed to replicate the results of the second SNP; the first was
replicated. These SNPs were associated with elevated systolic and diastolic blood pressures in
both populations. Once again, mitochondrial dysfunction is thought to be the culprit. Altered
PATHOGENIC PARK2 GENE ABERRATIONS 9

mitochondrial function has previously been implicated as a risk factor in developing high blood
pressure; researchers theorize that Parkin deficiency caused by PARK2 aberrations creates
excessive production of reactive oxygen species and mitochondrial calcium, which lead to
hypertension.
PARK2 and Cancer
Genetic variations in PARK2 have been implicated in a number of human cancers, most
significantly in colon cancer, lung cancer, and glioblastoma multiforme (GBM) (Veeriah, Taylor,
Meng, Fang, Yilmaz, Vivanco, & Chan, 2010). These cancers are related to multiple deletion
sites lying between 161,701,136 and 163,890,026. Veeriah et al. discovered that when PARK2 is
mutated in the germline (in other words, heritable genes) neuronal dysfunction occurs; when
PARK2 is mutated in non-neuronal somatic cells (those that are not heritable), tumor growth can
occur. This is believed to be related to PARK2s normal interaction with cyclin E, an enzyme
related to cell mitosis. PARK2 normally targets cyclin E for desctruction. When this process is
disrupted by genetic mutation, over production of cyclinE leads to impaired mitosis, which can
lead to tumor production. Thus, Veeriah et al. believe that they have identified PARK2 as a long-
sought tumor suppressor; they have already begun studies on altering deficient PARK2 genes in
an attempt to prevent and cure cancer.
PARK2 and Leprosy
Studies related to PARK2 irregularities and leprosy are interesting in that leprosy is
actually caused by contraction of Mycobacterium Leprae (Chopra, Ali, Srivastava, Aggarwal,
Kumar, Manvati, Bamezai, 2013). Thus, aberrations in PARK2 are not really seen as a cause
in Leprosy, but rather as a contributing factor to susceptibility. Independent studies in China,
PATHOGENIC PARK2 GENE ABERRATIONS 10

India, and Croatia have all found PARK2 SNPs identified as contributors to the susceptibility of
the disease; in fact, between 6:162,455,921 and 6:163,143,199 more than eighteen individual
SNPs have been found to be statistically significant. In Croatia, the genetically isolated
population of Mljet Island, a quarantine facility for persons with leprosy, SNPs located at
6:163,214,027 and 6:163,151,399 were found to be abundant (Bakija-Konsuo, Mulic, Boraska,
Pehlic, Huffman, Hayward, Rudan, 2011). In India, researchers discovered that leprosy
patients in northern India had distinctly different SNPs than leprosy patients in eastern India;
eleven SNPs associated with susceptibility to leprosy were identified in these two regions alone
(Chopra, et al., 2013).
The exact relationship between PARK2 SNPs and leprosy is unclear. Researchers
theorize that this relationship may be related to down-regulation of Parkin in macrophages (de
Lsleuc, Orlova, Cobat, Girard, Huong, Ba, Schurr, 2013). The human macrophage is a
natural host cell for the leprosy bacteria. It also usually functions as a mediator of the immune
system. The down-regulation of Parkin appears to be directly related to dysfunction of the
macrophage, leading to a decrease in interleukin-6 and chemoattractant protein 1; these
decreases appear to make it more difficult to fight leprosy.
PARK2 and Delayed Neuropsychological Sequelae After Carbon Monoxide Poisoning
One very interesting study on delayed neuropsychological sequelae following carbon
monoxide poisoning found that a SNP at 6:162382734 created susceptibility to these effects
(Liang, Li, Zhang, Zhang, Gu, Wang, Gu, 2013). Delayed neuropsychological sequelae
(DNS) are neurological symptoms that show up after some sort of neurological damage occurs;
in this case, carbon monoxide (CO) poisoning. Symptoms of DNS include gait and motor
PATHOGENIC PARK2 GENE ABERRATIONS 11

disturbances, cognitive impairments, anxiety, depression, and insomnia. Notably, these
symptoms do not always happen after CO poisoning occurs. It appears that the aforementioned
SNP is related to impaired recovery and higher incidents of DNS after CO poisoning. It is
interesting that both Parkinson disease and ASD also have symptoms of gait and motor
disturbance and cognitive impairment in some cases. PARK2 disruption seems to be related to
similar sets of symptoms across several different genetic phenotypes.
PARK2 and Attention-Deficit/Hyperactivity Disorder
While genome-wide genetic loci have not yet been identified in cases of ADHD,
researchers have identified rare copy number variations in PARK2 that occur more frequently in
ADHD patients than in control subjects (Jarik, Volckmar, Putter, Pechlivanis, Nguyen,
Dauvermann, Hinney, 2014). Recall that copy number variations can either create excess
genetic material or delete segments of genes. Between 6:162,659,756 and 6:162,767,019 Jerik et
al. discovered three deletions in nine duplications in patients with ADHD, compared to only two
deletions and two duplications in control subjects. While the exact relationship between these
rare copy number variations and ADHD remains unknown, Jerik et al. speculate that these
aberrations may increase susceptibility by affecting dopamine uptake.
PARK2 and Intellectual Disabilities
Rarely, subtelomeric deletion of the q arm of chromosome 6 occurs (Lee, Cho, Hallford,
2011). A subtelomere is the most distal region of unique DNA on a chromosome, as seen here:
PATHOGENIC PARK2 GENE ABERRATIONS 12


Recall that the PARK2 gene is also located on the terminal end of the q arm of
chromosome 6. Thus, when a deletion of the subtelomere occurs, PARK2 is involved. In fact,
Lee, Cho, and Hallford (2011) found that the break that causes the deletion usually occurs at
the FRA6E site previously identified as being part of PARK2.
When the subtelomere of chromosome 6 is deleted, severe forms of intellectual disability
occur. This may include developmental delay, dysmorphic features, seizure disorders, low
muscle tone, microcephaly (small head size), and underdevelopment of the corpus callosum.
Interestingly, many of these findings are sometimes seen in ASD, including intellectual disability
and developmental delay, low muscle tone, and seizure disorders.
PARK2 and Autism Spectrum Disorder
More than 180 gene mutations have at one time been identified as being related to ASD
(Girirajan, Dennis, Baker, Malig, Bradley, Coe, Eichler, 2013). Recently, multiple studies
have identified copy number variations in PARK2 as having a statistically significant relationship
in the development of ASD. Recurrent inherited mutations and de novo (non-inherited)
mutations have been observed in PARK2 in comparison to controls. One very specific case study
of two patients presenting with ASD found a copy number loss between 6:162,962,435 and
PATHOGENIC PARK2 GENE ABERRATIONS 13

6:163, 081,102 (Scheuerie & Wilson, 2011). This individual was originally diagnosed with
Asperger syndrome, a higher functioning form of ASD. The second patient, whose symptoms
were described as being more severe, particularly in cognitive impairment, was discovered to
have both an inversion of the p arm of chromosome 6 in addition to copy number gains in
PARK2 between 6:162,660,383 and 6:162,821,588. As the spectrum of ASD is so variant, it
would seem prudent that future studies focus on providing better description of symptoms along
with the specific genetic anomalies discovered.
PARK2 copy number variations were found in one study to belong to the ubiquitin gene
family (Glessner, Wang, Cai, Korvastka, Kim, Wood, Hakonarson, 2009). Researchers are
doing intensive studies in the role of ubiquitin-protein ligase and ASD. Brain studies of persons
with ASD show that they typically experience overgrowth of brain matter, leading to increased
brain size and disrupted neural pathways (Page, Daly, Schmitz, Simmons, Toal, Deeley,
Murphy, 2006). Perhaps researchers will one day find a link between the hampered ubiquitin-
protein ligase and excessive gray matter.
Proposed Areas of Further Research
While it is exciting to discover that so much information can be found about PARK2
anomalies and their phenotypic expressions, it is also clear that there is still much work to be
done. A clear theme throughout the research is the role of Parkin in protein ligase; future studies
should focus on better defining the exact nature of Parkin and the effects of dysfunctional protein
destruction.
In discovering the wide variety of disorders linked just to this one gene, it might be
interesting to do family case studies on aberrations in PARK2. For instance, in this writers
PATHOGENIC PARK2 GENE ABERRATIONS 14

family there are multiple persons with high blood pressure, multiple persons with diabetes,
several suspected cases of ADHD, and six known cases of ASD. Could PARK2 be the culprit?
It would be extremely interesting to study families with similar histories to see if one genetic
anomaly might account for multiple generations of disease.
Over time, the cost of genetic testing has begun to decline, while the availability of
genetic counselors is on the rise. If this trend continues, it might be feasible for couples to obtain
genetic counseling to before they attempt to conceive. Given that scientists are already able to
select genes in assisted conception, it might be possible to actually stop disease processes in
family lines before this occurs. Devastating genetic diseases such as Huntingtons and Tay
Sachs could be wiped out as effectively as if parents had been immunized, and future generations
could be protected.
Summary
The science of genetics only improves with time. As years go by and more and more
information is recorded, researchers are able to get much more detailed and specific in their
findings. There are 23 pairs of human chromosomes and this paper has examined genetic
aberrations of a single gene on just one of them. One hopes that as technology improves, we will
be able to gain a greater understanding of how disease processes might be impacted by genetics,
which may one day lead to unprecedented abilities to prevent and cure those disease.



PATHOGENIC PARK2 GENE ABERRATIONS 15

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PATHOGENIC PARK2 GENE ABERRATIONS 16

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