Genetics of AD and PD 715
Increased tendency for oligomer and aggregate formation in SNCA mutants has
been suggested to be a cause of PARK1-linked PD, and PARK4-linked PD multipli-
cations with an increased amount of normal α-synuclein may predispose neurons to
oligomer and aggregate formations (El-Agnaf et al., 1998; Fredenburg et al., 2007).
In LBs the α-synuclein protein is phosphorylated at serine 129 (Ser129) which is
located within the C-terminal that has been implicated as playing an important role
in aggregation (Bisaglia et al., 2008). Interestingly, in a Drosophila model, mutation
of Ser129 to alanine (which prevents phosphorylation) can suppress dopaminergic
neuronal loss (Chen and Feany, 2005).
Genetic Variation
Multiple SNCA mutations and multiplications have been described. Genetic vari-
ation in SNCA appears to contribute to PD phenotype. For example, PARK4
American and European families with SNCA triplication show different clinical
features from families with the SNCA duplication where the phenotype closely
resembles idiopathic PD, with late age of onset, slow progression, and no atypical
features, suggesting that SNCA gene dosage may play a role in disease progression
(Chartier-Harlin et al., 2004; Ibanez et al., 2004). SNCA duplications are rarely asso-
ciated with dementia (Fuchs et al., 2007; Nishioka et al., 2006). Multiplications of
SNCA appear to be slightly more common than missense mutations with the SNCA
triplication found in a large Iowan family (Singleton et al., 2003). Duplications of
SNCA (Chartier-Harlin et al., 2004; Ibanez et al., 2004; Nishioka et al., 2006)were
reported in a Swedish–American family (Fuchs et al., 2007) with patients in the
Swedish branch carriers of the duplication and those in the American branch carriers
of the triplication (Farrer et al., 2004), suggesting unequal recombination or cross-
ing over as the potential mechanisms for duplication and triplication, respectively
(Fuchs et al., 2007). Both the E46K mutation and the triplication are associated with
Parkinsonism and dementia, and the age of onset is younger than the other muta-
tions with diffuse Lewy body disease. A30P mutation is usually not associated with
dementia. The A53T mutation has been associated with dementia and the presence
of cortical Lewy bodies (Golbe, 1990; Golbe et al., 1990).

In addition, SNCA promoter polymorphisms have been associated with idiopathic
PD disease risk (Maraganore et al., 2006; Pals et al., 2004; Tan et al., 2004a),
and recently SNCA polymorphic mutations associated with increased α-synuclein
expression have been reported to be significant risk factors for sporadic PD (Mizuta
et al., 2006
; Mueller et al., 2005).
PARK8: LRRK2
Inheritance and Clinical Features
Autosomal dominant PARK8-linked PD was first identified in a Japanese family
known as the Samagihara kindred (Funayama et al., 2002). Clinical features were
first described in 1978 in a large Japanese family (Nukada et al., 1978) with simi-
lar symptoms as sporadic PD with a slightly earlier onset of age, and this linkage
has been replicated in Caucasian families (Zimprich et al., 2004). Although affected
716 L.M. Bekris et al.
individuals have clinically typical PD, pathologically the disease appears to be het-
erogeneous with reports of Lewy body pathology and tau pathology as well as
neuronal loss without intracellular inclusions (Nicholl et al., 2002; Wszolek et al.,
2004) in addition to motor neuron disease (Zimprich et al., 2004). Dementia is not
a common f eature but has been described in some families (Zimprich et al., 2004).
Gene Location and Structure
The gene for PARK8 was recently identified as Leucine Repeat Rich Kinase 2
(LRRK2; also called dardarin, from the Basque word for tremor) in families from
the Basque region of Spain, Britain, Western Nebraska, and in an American kin-
dred of German descent (Paisan-Ruiz et al., 2004; Zimprich et al., 2004). It is
located on chromosome 12p12 and is a huge gene encompassing 144 kb in the
genome, consisting of 51 exons (7449 bp cDNA) and encoding a protein consisting
of 2517 amino acids. The LRRK2 gene contains several functional domains includ-
ing ANK (ankyrin repeat domain), LRR (leucine-repeat-rich), ROC (Ras of complex
proteins), COR (carboxy terminal of ROC), MAPKKK (mitogen-activated protein
kinase kinase kinase), and a WD40 domain that is rich in tryptophan and aspartate

repeats.
Gene Function and Expression
Function of LRRK2 is not well known, although it has been identified as a tyro-
sine kinase-like protein (Mata et al., 2006). The ROC domain is able to bind GTP
and is essential for the MAPKKK domain to exert kinase activity but does not have
GTPase activity (Ito et al., 2007). Some of the LRRK2 mutations appear to exert
increased kinase activity (Gloeckner et al., 2006; West et al., 2005). Other functional
domains are believed to be important in protein–protein interactions (Zimprich et al.,
2004). LRRK2 also interacts with other familial PD proteins. For example, LRRK2
appears to interact with parkin through the ROC domain; however, the interaction
with parkin does not seem to enhance polyubiquitylation of LRRK2 (Smith et al.,
2005). LRRK2 expression has been described in the central nervous system (cerebral
cortex, medulla, cerebellum, spinal cord, putamen, and substantia nigra), heart, kid-
ney, lung, liver, and peripheral leukocytes (Paisan-Ruiz et al., 2004; Zimprich et al.,
2004). LRRK2 protein is found in the cytosol and mitochondrial outer membrane
(West et al., 2005), plasma membrane, lysosomes, endosomes, transport vesicles,
Golgi apparatus, a cytoskeleton protein microtubule, synaptic vesicles, and lipid
rafts (Biskup et al., 2006; Hatano et al., 2007). Interestingly, α-synuclein is also
expressed in the presynaptic membranes and lipid rafts (Fortin et al., 2004).
There is currently very limited postmortem data on pathogenic LRRK2 mutations
but it appears that typical LB pathology is seen in most LRRK2-related patients. One
report of LRRK2 brain expression shows substantia nigra cell loss, Lewy body for-
mation, and small numbers of cortical Lewy bodies (Khan et al., 2005). In the same
study18F-dopa positron emission tomography (PET) in another patient, but not in
unaffected family members, showed a pattern of nigrostriatal dysfunction typical
of idiopathic PD (Khan et al., 2005
). The mechanism that links LRRK2 protein to
Genetics of AD and PD 717
SNCA protein accumulation remains unknown, but evidence suggests that there may
be a direct interaction between LRRK2 and the SNCA protein (Silveira-Moriyama

et al., 2008; Smith et al., 2005).
Genetic Variation
Over 20 missense or nonsense mutations are concentrated in these functional
domains (Fig. 7) (Funayama et al., 2002;Mataetal.,2006; Paisan-Ruiz et al., 2004;
Zimprich et al., 2004). Several coding mutations have been identified in the LRRK2
gene including: Y1699C, R1441C, I1122V, I2020T, and R1369G and a splice site
mutation, 3342A. The most frequent mutation is G2019S that accounts for as many
as 40% of cases of Arab descent, about 20% of Ashkenazi Jewish patients, and is the
most frequent LRRK2 mutation in a large British kindred (Khan et al., 2005; Lesage
et al., 2006, 2005; Zabetian et al., 2006). LRRK2 mutations have also been reported
in some apparently sporadic PD patients (Gilks et al., 2005). One of these polymor-
phisms, G2385R, is a genetic risk factor for sporadic PD in Asian populations (Di
Fonzo et al., 2006; Funayama et al., 2002; Tan and Skipper, 2007). A mutation was
also identified in 5 out of 107 sporadic Spanish/Basque PD cases suggesting that
this gene may have a reduced penetrance. In addition, the mean age at onset (64
years) in a British kindred and the occurrence of mutations in apparently sporadic
PD patients suggests that mutations in this gene may be more widely distributed in
the late-onset PD population than the SCNA gene (Nicholl et al., 2002).
Fig. 7 PARK8: LRRK2 structure and mutations. ANK, ankyrin repeat region; LRR, leucine-rich
repeat domain; ROC, Ras of complex; COR, C-terminal of Ras (GTPase) (Tan et al., 2007). Scale
is approximate
PARK5: UCHL1
Inheritance and Clinical Features
PARK5-linked PD is an autosomal dominant PD. Clinical features are similar to
those of sporadic PD with the age of onset from 49 to 50. A mutation (I93M) has
718 L.M. Bekris et al.
been described in a single German PD family and named as the PARK5 locus (Leroy
et al., 1998). However, another study did not find an association with the I93M muta-
tion in familial PD (Harhangi et al., 1999). A S18Y polymorphism in the PARK5
gene has been associated with familial and sporadic PD in some studies but not oth-

ers, leading some to speculate that the PARK5 locus mutations may confer only a
weak effect on risk for the sporadic form of PD (Hutter et al., 2008; Levecque et al.,
2001; Maraganore et al., 1999; Mellick and Silburn, 2000; Wintermeyer et al., 2000;
Zhang et al., 2008).
Gene Location and Structure
The PARK5-linked PD gene has been reported as the ubiquitin carboxyl-terminal
hydrolase-L1 (UCHL1) located on chromosome 4p13 (Leroy et al., 1998). UCHL1
is a protein of 223 amino acids, 9 exons, and a transcript length of 1172 bps
(Wilkinson et al., 1989) (Fig. 8).
Fig. 8 PARK5: UCHL1 structure and mutations. In vitro assays demonstrate dimerization or
ubiquination inhibition by this molecule with α-synuclein at S18Y (inhibits dimerization with α-
synuclein leading to degradation of α-synuclein) and I93M (inhibits hydrolyzation and thus allows
dimerization with α-synuclein inhibiting degradation of α-synuclein) (Liu et al., 2002a). An active
site is present within a loop structure (ASL) as well as many other catalytic sites in other regions
not denoted here (Das et al., 2006). Scale is approximate
Gene Function and Expression
UCHL1 is an ubiquitin-recycling enzyme that hydrolyzes small C-terminal adducts
of polyubiquitine chains to generate ubiquitin monomers and is involved in the ubiq-
uitin proteosome system (Wilkinson et al., 1989). UCHL1 is highly expressed in
the brain, constituting up to 2% of total protein (Das et al., 2006; Wing, 2003).
Normally it is expressed exclusively in neurons and testis but abnormal expression
has been described in many primary lung tumors, lung tumor cell lines, and colorec-
tal cancer (Hibi et al., 1998; Sasaki et al., 2001; Yamazaki et al., 2002). Neuronal
functions include dimerization-dependent ubiquitin ligase activity (Liu et al., 2002a;
Wilkinson et al., 1989) and the maintenance of ubiquitin homeostasis by promoting
ubiquitin monomer stability (Osaka et al., 2003). There is also evidence that UCHL1
may modulate tubulin polymerization (Kabuta et al., 2008).
Postmortmem studies indicate that the UCHL1 protein is found in LBs of spo-
radic PD cases and that it can promote the accumulation of SNCA protein (Leroy
et al., 1998; Liu et al., 2002a). Therefore, further study of the pathogenesis and

potential role of UCHL1 in PD pathology may be warranted.
Genetics of AD and PD 719
Genetic Variation
The heterozygous I93M amino acid substitution in UCHL1 was identified in a
sibling pair, both affected by PD, and the transmitting parent was asymptomatic.
Functional studies show that UCHL1 I93M mutant protein has a 50% decrease in
hydrolytic activity in vitro (Leroy et al., 1998; Nishikawa et al., 2003) with cat-
alytic activity of half of the wild-type enzyme (Leroy et al., 1998), suggesting that
the supply of ubiquitin for 26S proteasome may be reduced with this mutation. The
I93M site is located within the hydrophobic core holding the structure of the right
lobe together, and even though subtle perturbation caused by substituting methio-
nine for isoleucine is unlikely to have significant structural consequences, it has
been suggested that any movement of this residue could possibly distort the geom-
etry of the catalytic triad located there (Das et al., 2006) (Fig. 8). It has also been
suggested that the I93M mutation inhibits hydrolyzation and thus allows dimeriza-
tion with α-synuclein inhibiting degradation of α-synuclein (Leroy et al., 1998;Liu
et al., 2002a). At 20 weeks of age, high-expressing I93M Tg mice show a significant
reduction in dopamine neurons in the substantia nigra and in dopamine content in
the striatum compared to the non-Tg mice. In addition, high-expressing I93M Tg
mice have an increased amount of insoluble UCHL1 in the midbrain, suggesting a
toxic gain of function (Setsuie et al., 2007). Deletion of UCHL1 exons 7 and 8 in
a mouse model causes gracile axonal dystrophy (gad mouse); this is an autosomal
recessive condition characterized by axonal degeneration and formation of spheroid
bodies in motor and sensory nerve terminals (Saigoh et al., 1999). UCHL1 binds to
and stabilizes monoubiquitin in neurons (Osaka et al., 2003). The I93M mutation
in UCHL1 alters the conformation of UCHL1 (Naito et al., 2006; Nishikawa et al.,
2003). An incidental mutant, the gracile axonal dystrophy mouse lacks functional
UCHL1 due to an intragenic exonic deletion. In these mice, UCHL1 dysfunction
appears to disturb the reuse of free ubiquitin, which results in the accumulation of
abnormal proteins in the brain. Mice deficient in UCHL1 do not exhibit obvious

dopaminergic cell loss, in contrast to UCHL1I93M-transgenic mice (Osaka et al.,
2003; Saigoh et al., 1999; Setsuie et al., 2007), suggesting that a loss or decrease
in the level of UCHL1 is not the main cause of PD and that I93M-associated PD
is caused by an acquired toxicity. Thus, although the hydrolase activity of I93M is
decreased (Leroy et al., 1998; Nishikawa et al., 2003), this decreased activity may
not be a major cause of PD.
An UCHL1 S18Y variant has been described that may be associated with a
decreased risk of idiopathic PD (Healy et al., 2004b; Maraganore et al., 2004;
Tan et al., 2006a). Although close analysis of consequences of the S18Y on pro-
tein structure did not yield any insight on the functional impact of this mutation
(Das et al.,
2006), in vitro studies indicate that the S18Y variant has reduced ligase
activity and possibly increased hydrolase activity compared with wild-type enzyme
(Liu et al., 2002a; Nishikawa et al., 2003). It has been suggested that the S18Y
site may inhibit dimerization with α-synuclein leading to the degradation of α-
synuclein and thus less accumulation in brain (Liu et al., 2002a; Setsuie and Wada,
2007).
720 L.M. Bekris et al.
PARK13: HTRA2
Inheritance and Clinical Features
The PARK13 locus was identified in a German idiopathic PD case-control s tudy
(Strauss et al., 2005). The PARK13 gene encodes HtrA serine peptidase 2 ( HTRA2)
and is located on chromosome 2p13.1 (Strauss et al., 2005). Two gene variants,
A141S and G399S, were identified in the German PD case-control study, and these
variants resulted in a defective activation of protease activity and mitochondrial dys-
function in vitro (Strauss et al., 2005). However, further studies are necessary to
determine if this is a new familial PD-inducing protein.
Gene Location and Structure
AcDNAofHTRA2 was first isolated by Faccio et al. (2000a,b). It has 8 exons with
a transcript length of 2367 bps that encodes a protein called HTRA2 consisting of

458 amino acids and homology to bacterial HtrA endoprotease with a PDZ domain
(Faccio et al., 2000a, b; Vande Walle et al., 2008) (Fig. 9).
Fig. 9 PARK13: HTRA2 structure and mutations. The PDZ domain helps anchor transmembrane
proteins to the cytoskeleton. Mutations A141S, S276C, and G399S are shown (Strauss et al., 2005;
Vande Walle et al., 2008). TM, transmembrane domain. Scale is approximate
Gene Function and Expression
HTRA2 is a nuclear-encoded protein located in the intermembrane space of the
mitochondria and released into the cytosol during apoptosis. It has a serine pro-
tease domain that interacts with inhibitor apoptosis proteins (IAPs) to enhance the
progression of apoptosis (Althaus et al., 2007; Hegde et al., 2002; Li et al., 2002;
Martins et al., 2002; Srinivasula et al., 2003; Suzuki et al., 2001; Takahashi et al.,
1998; Verhagen et al., 2002; Yang et al., 2003). Upon receiving various apoptotic
stimuli it is released from the mitochondrial intermembrane space into the cytosol,
where it is thought to induce apoptotic cell death by binding to IAPs. The binding
of HTRA2 to IAP appears to block the caspase-inhibitory activities of IAPs (Althaus
et al., 2007; Hegde et al., 2002;Lietal.,2002; Martins et al., 2002; Srinivasula et al.,
2003; Suzuki et al., 2001; Takahashi et al., 1998; Verhagen et al., 2002; Yang et al.,
2003). HTRA2 also enhances caspase activity by contributing to permeabilization
of the mitochondrial outer membrane, which leads to the release of cytochrome c
(Suzuki et al., 2001).
Mouse models with loss of HTRA2 activity show a Parkinsonian phenotype with
striatum-specific neuronal loss (Jones et al., 2003; Martins et al., 2004) and may
Genetics of AD and PD 721
suggest that other stress response proteins, in addition to IAPs, are involved in
HTRA2 associated neuronal loss, including the transcription factor CHOP (Moisoi
et al., 2008).
Genetic Variation
Three HTRA2 mutations have been reported: A141S, G399S, and S276C (Fig. 9).
The HTRA2 G399S mutation induces mitochondrial dysfunction in vitro and is asso-
ciated with altered mitochondrial morphology whereby cells overexpressing G399S

mutant HTRA2 are more susceptible to stress-induced cell death than wild-type
(Strauss et al., 2005; Vande Walle et al., 2008). The S276C mutation i s the cause of
the mouse mutant mnd2 (motor neuron degeneration 2) phenotype, which exhibits
muscle wasting, neurodegeneration, involution of the spleen and thymus, and death
by 40 days of age. Striatal neuron degeneration, with astrogliosis and microglia acti-
vation, begins at around three weeks of age, and other neurons are affected at later
stages (Jones et al., 2003).
2.2.3 Genes Associated with Autosomal Recessive Parkinson’s Disease
PARK2: PRKN
Inheritance and Clinical Features
Clinical features of the autosomal recessive young onset PARK2-linked PD include
an age of onset between 20 and 40, but the age of onset can be earlier than
10 years and above 60 years (Yamamura et al., 1973).When the age of onset is
young, dystonia is a characteristic symptom and patients are levodopa responsive.
Motor fluctuations soon develop. Pathologically, the substantia nigra undergoes
severe neuronal loss and gliosis whereas the locus ceruleus is much less severely
involved and usually no Lewy bodies are seen (Mori et al., 1998; Takahashi et al.,
1994), although rare Lewy body positive cases have been reported (Farrer et al.,
2001).
Gene Location and Structure
Linkage analysis of several PD families mapped the PARK2 disease locus to chro-
mosome 6q26, near the sod2 locus (Jones et al., 1998; Matsumine et al., 1997; Tassin
et al., 1998). By screening a BAC library using the D6S305 marker at this region
a cDNA was cloned consisting of the open reading frame of the novel gene PRKN
(Kitada et al., 1998). PRKN protein belongs to the RING-IBR-RING family, which
is a subgroup of RING finger type E3 ubiquitin ligase. The PRKN protein is 465
amino acids, with 12 exons and a 1395 bp open reading frame. It contains two RING
finger domains at the carboxyl (C) terminus. RING stands for r are interesting gene
and RING-like structures have been found in proteins with ubiquitin ligase activity
(Lorick et al., 1999). Similar to other RING finger proteins, the PRKN protein has

been found to function as an E3 ubiquitin ligase (Shimura et al., 2000).
722 L.M. Bekris et al.
Gene Function and Expression
PRKN appears to be a cytosolic protein normally, but it may also colocalize to
synaptic vesicles, the Golgi complex, endoplasmic reticulum, and the mitochon-
drial outer membrane (Darios et al., 2003; Kubo et al., 2001; Mouatt-Prigent et al.,
2004; Shimura et al., 2000). Many of the single amino acid substitutions appear to
alter wild-type PRKN cellular localization, solubility, and propensity to aggregate
(Cookson et al., 2003; Gu et al., 2003; Wang et al., 2005). It has been reported that
parkin binds tubulin and associates with microtubules (Ren et al., 2003). However,
PD-linked mutations, including those that impair E3 activity (Matsuda et al., 2006),
appear not to affect this binding activity (Yang et al., 2005). Many ubiquitination
substrates have been proposed including the aminoacyl-tRNA synthetase cofac-
tor, p38, and a rare, 22-kDa glycosylated form of α-synuclein (Corti et al., 2003;
Shimura et al., 2001; von Coelln et al., 2004a). Some mutations appear to result in
PRKN loss of function, although PRKN knock-out mice have only subtle behavior
and glutaminergic transmission alterations and do not suffer nigral neuronal degen-
eration or clinical manifestations of Parkinsonism (Goldberg et al., 2003; Itier et al.,
2003) and reduced numbers of noradrenergic neurons in the locus ceruleus were
reported in one strain (Von Coelln et al., 2004b). Accumulation of p38 leading to cat-
echolaminergic cell death has been shown in one strain as well as in PARK2-linked
PD and idiopathic PD brain (Ko et al., 2005).
PRKN knock-out mice also have reduced numbers of mitochondrial oxidative
phosphorylation proteins, a decrease in mitochondrial respiratory capacity, and age-
dependent increases in oxidative damage (Palacino et al., 2004). Mitochondrial
defects have also been reported in parkin knock-out Drosophila, suggesting that
PRKN ubiquination dysfunction may be secondary in the course of pathogenic
events (Greene et al., 2003; Pesah et al., 2004). In vitro studies of a PRKN knock-
down SH-SY5Y cell line showed apoptotic cell death and an increase in the
auto-oxidized forms of levodopa and dopamine, implicating parkin antioxidative

properties (Machida et al., 2005).
PARK2-linked recessive, loss-of-function mutations do not usually exhibit the
classical Lewy body pathology seen in idiopathic disease, although this is not the
case for some mutations that reduce but not completely ablate PRKN activity. In
addition, it appears that PRKN need not be mutated to participate in t he pathogenic
process because it is also found in the Lewy bodies of idiopathic disease brain
(Schlossmacher et al., 2002). Interestingly, Lewy bodies have been reported in
a patient carrying an R275W substitution and an exon 3 deletion (Farrer et al.,
2001), and an autopsy in a 73-year-old patient carrying a deletion of exon 7 as
well as the del1072T point deletion showed PD-type cell loss, reactive gliosis, and
SNCA-positive Lewy bodies (Pramstaller et al., 2005).
Genetic Variation
Reported mutations in parkin now exceed 100 including missense and nonsense
mutations as well as exonic deletions, rearrangements, and duplications (Abbas
et al., 1999; Hattori et al., 1998; Hedrich et al., 2002; Kann et al., 2002
; Klein
Genetics of AD and PD 723
Fig. 10 PARK2: PRKN structure. The general protein structure of parkin is shown (Schlehe
et al., 2008). More than 100 mutations have been identified and are not shown here. Five com-
mon alterations account for 35% of all PRKN mutations: (1) deletions of exon 4 (n = 28), (2)
deletions of exon 3 (n = 27), (3) deletions of exons 3–4 (n = 23), (4) a point mutation in exon 7
(924C>T; n = 38), and (5) a single base pair deletion in exon 2 (255/256delA; n = 17). Hotspots
for common parkin mutations appear to be concentrated in exons 2–7, whereas hotspots for exon
rearrangements are more likely to occur in introns 2–4 (Hedrich et al., 2004). Scale is a pproximate
et al., 2003, 2000). Exonic deletions in the parkin gene were first identified in
Japanese families with autosomal recessive juvenile Parkinsonism (Kitada et al.,
1998). Parkin mutations have been found to account for about 50% of familial cases
and about 70% of sporadic cases with age of onset of 20 years depending on the
ethnicity of the population sample (Lucking et al., 2000; Mata et al., 2004; Periquet
et al., 2003). Parkin mutational frequency in late-onset PD is lower than early-onset

cases, accounting for between 0 and 11% depending largely on whether the sample
is familial or sporadic (Foroud et al., 2003; Mata et al., 2004; Oliveri et al., 2001).
Many PRKN mutations including deletion mutations and point mutations have
been detected in the PRKN gene of PARK2-linked patients. The site of these
mutations spans almost all regions including the N-terminal UBL domain and the
RING-IBR-RING domain (Fig. 10) but there seems to be very little difference in
symptom phenotypes among these mutation sites, suggesting that the entire region
of the PRKN protein may be essential for exerting its physiology. PRKN-linked PD
has been initially characterized as a recessively inherited disease with a deleterious
alteration on both alleles with the presumption that heterozygous carriers are unaf-
fected. However, evidence now suggests that a large proportion of the total number
of cases identified with a parkin mutation have only a single heterozygous mutation
(Lucking et al., 2000; Mata et al., 2004; Periquet et al., 2003). Thus patients having
a loss of one PRKN allele may suffer from haploinsufficiency as a consequence of
a reduced PRKN expression or enzymatic activity. Indeed, one brain imaging study
showed that some asymptomatic heterozygous PRKN carriers show significant stri-
atal dopaminergic dysfunction, suggesting there may be a gene dosage effect (Kann
et al., 2002). In addition, other reports suggest that PRKN heterozygous mutation
carrier status significantly influences age at onset of PD (Foroud et al., 2003) with
many of the heterozygous mutations in the first RING finger domain associated with
later age of onset (Oliveira et al., 2003). A common polymorphism in the PRKN pro-
moter has been associated with late-onset idiopathic disease (Tan et al., 2005a;West
et al., 2002).
Differential expression of a PRKN splice variant where the RING domains
have been deleted has also been shown to modulate the risk of sporadic PD (Tan
et al., 2005b). In one family, patients with a recessive pattern of inheritance for the
PRKN Ex3-40 mutation manifest symptoms of early-onset levodopa-responsive
724 L.M. Bekris et al.
Parkinsonism whereas in other families with the same mutation, an autosomal dom-
inant pattern of inheritance is present (Munoz et al., 2002; Tan et al., 2003). Some

reports suggest that carriers of PRKN mutations are more likely to have dystonia
and symmetric symptoms than noncarriers, and some may even have atypical fea-
tures such as psychiatric manifestations (Khan et al., 2003; Lucking et al., 2000).
However, a wide overlap of Parkinsonian symptoms between some groups suggests
that no specific diagnostic clinical feature can be demonstrated (Munhoz et al.,
2004). Thus the influence of the PRKN gene on PD risk may involve a complex
interplay between environment and gene dose that manifests varying phenotypes.
In summary, over 100 different mutations have been identified in the parkin gene
including, but not limited to, 40 exon rearrangements (26 deletions and 14 multi-
plications), 43 single base pair substitutions, and 12 small deletions or insertions of
one or several base pairs. The most common mutations appear to be (1) deletions
of exon 4 (n = 28), (2) deletions of exon 3 (n = 27), (3) deletions of exons 3–4 (n
= 23), (4) a point mutation in exon 7 (924C>T; n = 38), and (5) a single base pair
deletion in exon 2 (255/256delA; n = 17). These five common alterations account
for 35% of all parkin mutations. Hotspots for common parkin mutations appear to
be concentrated in exons 2 and 7, whereas hotspots for exon rearrangements are
more likely to occur in introns 2 through 4 (Hedrich et al., 2004) (Fig. 10).
PARK7: DJ1
Inheritance and Clinical Features
DJ1 recessively inherited missense and exonic deletion mutations were first identi-
fied in two European families with an age of onset of 20–40 years (Bonifati et al.,
2003). PARK7-linked PD appears to be very rare (Bonifati et al., 2003; Hague et al.,
2003; Hering et al., 2004). Very few DJ1 patients have been reported in the litera-
ture, thus clinical features and correlations with DJ1 mutations are still difficult
to determine. Some clinical features such as psychiatric symptoms (Dekker et al.,
2003), short stature, and brachydactyly (Dekker et al., 2004) have been reported.
DJ1 mutations rarely associate with PD but some missense, splice-site, and exonic
deletion mutations have been identified, accounting for less than 1% of early-onset
PD (Clark et al., 2004; Hering et al., 2004; Lockhart et al., 2004; Tan et al., 2004b).
Gene Location and Structure

DJ1 has been cloned and is located on chromosome 1p36.23. It has a transcript
length of 949 bps with seven exons (Nagakubo et al., 1997). It encodes a protein
consisting of 189 amino acids.
Gene Function and Expression
DJ1 is a homodimer that belongs to the peptidase C56 family of proteins (Moore
et al., 2003). It is a cytoplasmic protein, but it can also translocate into the mito-
chondria (Zhang et al., 2005) and it appears to act as an antioxidant (Abou-Sleiman
et al.,
2003; Canet-Aviles et al., 2004; Moore et al., 2005; Nagakubo et al., 1997).