Genetics of AD and PD 725
Its antioxidant properties may depend on a cysteine residue at 106, which upon oxi-
dation forms a disulphide bond (Canet-Aviles et al., 2004). DJ1 may act as either a
redox sensor protein that can prevent the aggregation of α-synuclein or an antioxi-
dant (Batelli et al., 2008; Canet-Aviles et al., 2004; Mitsumoto and Nakagawa, 2001;
Mitsumoto et al., 2001; Zhou and Freed, 2005; Zhou et al., 2006). DJ1 may also act
as a reactive oxygen species scavenger through auto-oxidation (Taira et al., 2004).
Thus, it has been proposed that inasmuch as substantia nigral neurons are exposed
to high oxidative stress owing to the presence of dopamine, DJ1may be acting as a
strong antioxidative protein.
Expression of DJ1 is ubiquitous and abundant in most mammalian tissues includ-
ing the brain, where it is found in both neuronal and glial cells (Bandopadhyay
et al., 2004). Downregulation of endogenous DJ1 protein of the neuronal cell line by
siRNA enhances oxidative stress-induced cell death, ER stress, and proteasome inhi-
bition, but not by proapoptotic stimulus (Taira et al., 2004; Yokota et al., 2003). The
L166P mutant protein has a reduced antioxidative activity (Takahashi-Niki et al.,
2004). Mutant DJ1 appears to interact with parkin (Moore et al., 2005) whereby
parkin acts as an E3 ligase to remove mutated DJ1. DJ1-null mice are sensitive to
oxidative stress and MPTP (Kim et al., 2005). DJ1 protein expression is increased
upon oxidative stress induced by paraquat (Mitsumoto et al., 2001). Other DJ1
knock-out strains show normal numbers of dopaminergic neurons but also sensi-
tivity to the PD associated environmental toxins paraquat and rotenone (Goldberg
et al., 2005; Meulener et al., 2005).
DJ1 does not appear to be an essential component of LBs in sporadic cases
(Bandopadhyay et al., 2004). DJ1 mutations are rare in sporadic PD but recent stud-
ies s uggest t hat DJ1 may play an important role in common forms of the disease.
Sporadic PD brain exhibits DJ1 with oxidative damage (Choi et al., 2006). Sporadic
PD patients also demonstrate a significant increase in total cerebrospinal fluid DJ1
protein levels compared to normal controls (Waragai et al., 2006).
Genetic Variation
In general, DJ1 mutations are found in the homozygous or compound heterozygous

state, putatively resulting in a loss of protein function. The L166P mutation causes
destabilization through unfolding of the C-terminus, inhibiting dimerization, and
enhancing degradation by the proteasome (Miller et al., 2003
; Moore et al., 2003;
Olzmann et al., 2004). In addition, probably consequential to instability, L166P
reduces the neuroprotective function of DJ1 (Taira et al., 2004). Reduced nuclear
localization, in favor of the mitochondria, is also seen for L166P, as well as for the
M26I and D149A mutations (Bonifati et al., 2003; Xu et al., 2005). In addition,
there appear to be structural perturbations associated with DJ1mutations L166P,
E64D, M26I, A104T, and D149A, which can lead to global destabilization, unfold-
ing of the protein structure, heterodimer formation, or reduced antioxidant activity,
implicating these mutations in pathogenicity associated with DJ1 (Anderson and
Daggett, 2008; Malgieri and Eliezer, 2008; Takahashi-Niki et al., 2004) (Fig. 11).
726 L.M. Bekris et al.
Fig. 11 PARK7: DJ1 structure and mutations. DJ1 mutations are found in both the homozygous
or heterozygous state, putatively resulting in a loss of protein function. Scale is approximate
PARK6: PINK1
Inheritance and Clinical Features
Mutations in the phosphatase and Tensin (PTEN) Induced Kinase 1 gene (PINK1)
were first identified in patients with recessive young-onset autosomal recessive PD
designated as PARK6. The age of onset is from 32 to 48 years (Valente et al., 2001).
PINK1 mutations account for approximately 1–7% of autosomal recessive PD in
Caucasians (Healy et al., 2004a; Rohe et al., 2004; Valente et al., 2001), about 8.9%
of autosomal recessive PD in Japanese autosomal recessive PD families (Li et al.,
2005), and 2–3% of sporadic and familial PD in individuals of Chinese origin (Tan
et al., 2006b, 2005c). Clinical features of PARK6 are similar to late-onset PD, with
rare features such as dystonia at onset, sleep benefit, and psychiatric disturbances
(Hatano et al., 2004b; Tan et al., 2006b; Valente et al., 2001). Clinical characteris-
tics of PINK1 are similar to PRKN with dystonia at onset and increased reflexes that
were originally thought to be related only to parkin (Ibanez et al., 2006). However,

age at onset is earlier in PINK1 mutational carriers than in those with PRKN muta-
tions (Leutenegger et al., 2006; Valente et al., 2001). Brain imaging of PARK6
carriers indicates a 20–30% reduction of the caudate and putamen (Khan et al.,
2002).
Gene Location and Structure
PINK1 is located on chromosome 1p36.12 and has eight exons and cDNA that
spans 1.8 kb. It encodes a protein with 581 amino acids. It has a serine/threonine
protein kinase domain. However, its function is not known (Valente et al., 2001).
It is a mitochondrial protein located in the matrix and the intermembrane space
that is ubiquitously expressed in the brain and systemic organs and contains
a mitochondrial-targeting motif and a conserved serine/threonine kinase domain
(Silvestri et al., 2005).
Gene Function and Expression
Functional studies have shown that PINK1 can be localized to mitochondria both
in vitro and in vivo (Gandhi et al., 2006). Wild-type PINK1 appears to be impor-
tant in neuroprotection against mitochondrial dysfunction and proteasome-induced
apoptosis whereas the G309D mutation impairs this protective effect, possibly by
interfering with adenosine diphosphate (ADP) binding and thus inhibiting kinase
activity (Valente et al., 2004, 2001). E240K and L489P mutants disrupt PINK1’s
Genetics of AD and PD 727
protectivity by either enhancing the instability of the protein or disrupting the
kinase activity of the protein (Petit et al., 2005). In vitro studies indicate that cells
transfected with PINK1 mutants have disrupted mitochondrial membrane poten-
tial under stressful conditions (Abou-Sleiman et al., 2006). Knock-out models of
the Drosophila PINK1 orthologue have defects in mitochondrial morphology and
increased sensitivity to oxidative stress and appear to be rescued by human parkin
(Clark et al., 2006).
PINK1 haploinsufficiency may be sufficient to cause disease because PINK1
is detected in some LBs in sporadic PD, as well as in samples carrying only one
mutant PINK1 allele, which are clinically and pathologically indistinguishable from

sporadic cases (Gandhi et al., 2006).
Genetic Variation
The first mutations discovered were the G309D missense and a W437X truncat-
ing mutation found in families of Italian and Spanish descent (Valente et al., 2004,
2001). Several point mutations, frameshifts, and truncating mutants have been iden-
tified (Bonifati et al., 2005; Ibanez et al., 2006; Tan et al., 2006b). Interestingly,
in contrast to PRKN, most of the PINK1 mutations reported are either missense
or nonsense mutations (Hatano et al., 2004a, b;Lietal.,2005; Rohe et al., 2004;
Valente et al., 2004). One family with a large deletion mutation involving exons 6–8
homozygotes has been reported (Li et al., 2005).
Japanese and Israeli PINK1-linked families and a sporadic PD patient of Chinese
ethnicity have a R246X mutation (Tan et al., 2006b). Most of the reported muta-
tions are located in a highly conserved amino acid position in the protein kinase
domain and are absent in healthy controls, thus suggesting that these mutations
are pathogenic (Abou-Sleiman et al., 2006) and that homozygous mutation carriers
appear to be clinically affected whereas heterozygous carriers are not (Hiller et al.,
2007). A large kindred from Sudan with early-onset Parkinsonism (ages 9–17 years)
is associated with a novel mutation, A217D, in the PINK1 gene. Phenotypes in this
family vary from dopa-responsive dystonia-like to typical early-onset Parkinsonism.
A217D is located in the highly conserved adenosine triphosphate orientation site
of the PINK1 kinase domain (Leutenegger et al., 2006; Tan and Skipper, 2007)
(Fig. 12).
PARK9: ATP13A2
Inheritance and Clinical Features
Homozygous and compound heterozygous mutations in the P-type ATPase gene
(ATP13A2) have been demonstrated in a Jordanian family (Myhre et al., 2008;
Najim al-Din et al., 1994) and a Chilean family (Ramirez et al.,
2006) with
Kufor–Rakeb syndrome, a form of recessively inherited atypical Parkinsonism that
is clinically characterized by very early age of onset (11–16 years), levodopa-

responsive Parkinsonism, pyramidal signs, dementia, and a supranuclear gaze palsy
(Najim al-Din et al., 1994, Williams et al., 2005). MRIs show significant atrophy of
the globus pallidus and the pyramids, as well as generalized brain atrophy in later
728 L.M. Bekris et al.
Fig. 12 PARK6: PINK1 structure and mutations. Many PINK1 mutations have been described of
which a few are shown. For a more complete list of PINK1 mutations, see Tan et al., (2007). MTS,
mitochondrial t argeting sequence; TM, transmembrane domain; STKD, serine threonine kinase
domain (Tan et al., 2007). Scale is approximate
stages. Some develop facial–faucial–finger minimyoclonus, visual hallucinations,
and oculogyric dystonic spasm (Williams et al., 2005).
Gene Location and Structure
The disease locus designated as PARK9 was mapped to 1p36.13 with a maxi-
mum LOD score of 3.6.1p36.13 is, a hotspot for autosomal recessive familial PD
(Hampshire et al., 2001). The disease gene was subsequently identified as ATP13A2.
The transcript has 29 exons and is 3854 bps in length. The ATP13A2 protein
contains 1180 amino acids and has 10 transmembrane domains.
Gene Function and Expression
ATP13A2 is a lysosomal membrane protein with an ATPase domain (Ramirez et al.,
2006). It is a member of the P5 subfamily of ATPases that transports inorganic
cations and other substrates. The exact function of the ATP13A2 protein is still
unknown. ATP13A2 is predominantly expressed in brain tissues, and ATP13A2
mRNA levels are about tenfold higher in the substantia nigra dopaminergic neurons
of sporadic patients than control subject brains (Ramirez et al., 2006).
Genetic Variation
All known ATP13A2 mutations appear to directly or indirectly affect transmembrane
domains (Ramirez et al., 2006) (Fig. 13). In vitro evidence indicates that wild-type
Genetics of AD and PD 729
Fig. 13 PARK9: ATP13A2 structure and mutations. Mutations found in young-onset PD (T12M,
G504R, and G533R; Di Fonzo et al., 2007) and Kufor-Rakeb syndrome PD (1306+5G/A,
1632_1653dup22, 3057delC; Ramirez et al., 2006) are shown. TM, transmembrane domain. Scale

is approximate
ATP13A2 is localized to the lysosome membrane of transiently transfected cells
whereas unstable truncated mutants are retained in the endoplasmic reticulum and
degraded by the proteasome (Ramirez et al., 2006). A homozygous missense muta-
tion (G504R) has been identified in one sporadic case from Brazil with juvenile
Parkinsonism (Di Fonzo et al., 2007). This patient had symptoms onset at age 12,
levodopa-responsive severe akinetic-rigid Parkinsonism, levodopa-induced motor
fluctuations and dyskinesias, severe visual hallucinations, supranuclear vertical gaze
paresis, and moderate diffuse atrophy but no pyramidal deficit nor dementia. In this
same study, two Italian cases with youth-onset PD without atypical features carried
a novel missense mutation (T12M, G533R) in a single heterozygous state (Di Fonzo
et al., 2007). A rare variant associated with an increased risk of PD among ethnic
Chinese in Asia has recently been described that has a clinical phenotype and brain
image similar to that seen in idiopathic PD (Lin et al., 2008).
GBA
Inheritance and Clinical Features
An association between mutations within the glucocerebrosidase gene (GBA) and
PD has been reported in multiple studies including an initial study where a small
group of PD postmortem brain samples were found to have a GBA mutation fre-
quency of 14% and where an Israeli PD patient sample was found to have a
GBA mutation frequency of 31.3% (Aharon-Peretz et al., 2004). The frequency for
GBA mutations appears to be less than 1% in the general population and 6–7% in
Ashkenazi Jews (Aharon-Peretz et al., 2004; Bras et al., 2007; Clark et al., 2005,
2007; De Marco et al., 2008; Eblan et al., 2006; Gan-Or et al., 2008; Lwin et al.,
2004; Nichols et al., 2009; Sato et al., 2005; Spitz et al., 2008; Tan et al., 2007;Toft
et al., 2006; Wu et al., 2007; Ziegler et al., 2007).
730 L.M. Bekris et al.
A family history of Parkinsonism is often reported in patients with Gaucher’s
disease (GD) (OMIM #606463), which is an autosomal recessive disorder caused
by mutations in GBA (Neudorfer et al., 1996). GD is a lysosomal storage dis-

ease characterized by an accumulation of glucocerebrosides (Goker-Alpan et al.,
2008). Clinical features of PD have been reported in a subset of patients with GD
(Neudorfer et al., 1996). Patients with GD (which affects the skeletal, hematologi-
cal, and nervous systems with varying severity) and Parkinsonism have early-onset,
levodopa-unresponsive disease with occasional cognitive decline (Wong et al.,
2004). Recent studies show that the neuropathological features associated with GBA
mutations include a variety of LB synucleinopathies, including LBs in the hip-
pocampus, suggesting that the clinical phenotype of PD with GBA mutations may
be diverse (Goker-Alpan et al., 2008; Mata et al., 2008).
Gene Location and Structure
GBA is located on chromosome 1 (1q21). The GBA cDNA is approximately 2 kb in
length (Horowitz et al., 1989; Reiner et al., 1988). A GBA pseudogene has a 96%
homology to GBA and is located approximately 12 kb downstream. There are two
in-frame translational start sites in exon 1 and exon 2. Initiation at each exon leads to
a different leader sequence but both are processed into a mature functional enzyme
of the same length. The protein is cleaved to produce a mature polypeptide of 497
amino acids with a molecular weight of 55.5 kDa. The polypeptide contains five
potential glycosylation sites, four of which appear to be glycosylated. The active
site of this enzyme resides in the C-terminal half of the molecule at exon 9 and exon
10 (Dinur et al., 1986).
Gene Function and Expression
The GBA gene encodes the lysosomal membrane protein, glucocerebrosidase, which
cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycol-
ipid metabolism (Dinur et al., 1986). GBA mRNA levels vary among cell lines,
with high, moderate, low, and negligible levels reported in epithelial, fibroblast,
macrophage, and B-cell lines, respectively (Reiner and Horowitz, 1988; Reiner
et al., 1987; Wigderson et al., 1989). There appears to be a poor correlation between
the levels of mRNA and the amount of identified enzymatic activity (Doll and Smith,
1993; Reiner and Horowitz, 1988) implicating a complex regulatory system for
the expression of glucocerebrosidase at the level of transcription, translation, and

posttranslational modification (Xu et al., 1995).
Genetic Variation
Over 250 mutations have been reported in GBA: 203 missense mutations, 18 non-
sense mutations, 36 small insertions or deletions that lead to either frameshifts or
in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying
two or more mutations in cis (Hruska et al., 2008). Recombination events with a
Genetics of AD and PD 731
highly homologous pseudogene downstream of the GBA locus also have been iden-
tified, resulting from gene conversion, fusion, or duplication. Some of the alleles for
disease mutations are also found in the pseudogene, making analysis complicated.
The GBA mutations that influence GD or PD are not necessarily disease-specific.
For example, N370S and L444P are the most common mutations associated with
both GD and PD whereas, in contrast, R120W is found mainly in PD but not GD,
and R463C is found mainly in GD but not PD (Aharon-Peretz et al., 2004;Bras
et al., 2007; Clark et al., 2005, 2007; De Marco et al., 2008; Eblan et al., 2006;
Gan-Or et al., 2008; Hruska et al., 2008; Lwin et al., 2004; Sato et al., 2005; Spitz
et al., 2008; Tan et al., 2007;Toftetal.,2006; Wu et al., 2007; Ziegler et al., 2007)
(Fig. 14).
Fig. 14 GBA structure and mutations. Over 250 GBA mutations have been described (Hruska
et al., 2008). Mutations found in PD include R120W, N370S, and L444P. The enzyme’s active site
is located in the region of mutations; N370S (exon 9) and L444P (exon 10). Scale is approximate
2.3 Summary
Thirteen loci have been linked to PD of which eight genes have been described:
four autosomal dominant (SNCA, LRRK2, UCHL1, and HTRA2) and four autoso-
mal recessive (PRKN, DJ1, PINK1, and ATP13A2). In addition, another gene has
recently been described as a robust risk factor for PD (GBA). These findings sug-
gest that PD pathology involves a strong genetic component and provides numerous
clues to the etiology of the disease. The function of these genes and their contri-
bution to PD pathogenesis remains unclear. However, many of these genes play a
role in ubiquitination, oxidative stress, and apoptosis, suggesting that PD, may be

a genetically complex and heterogeneous disease. In addition to the link between
these genes and familial forms of PD, many are also candidate genes for idiopathic
forms of the disease suggesting that some of these genes carry other mutations that
simply increase risk.
Acknowledgments This work is supported in part by the Office of Research and Development,
Biomedical Laboratory Research Program, U.S. Department of Veterans Affairs; the Mental Illness
Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System; the
Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care
System; and the University of Washington Alzheimer’s Disease Research Center, NIA AG005136.
732 L.M. Bekris et al.
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