**6. Sporadic PD**

Sporadic PD is multifactorial, complex and polygenic, generally determined by several common non-coding genetic variants, each of them play a role as a very modest risk factor singularly but with an important cumulative effect taken all together, interacting with environmental factors, other genes or functional variants, controlling the expression, splicing, phosphorylation, influencing the age at onset, severity and progression of the syndrome.

Association studies have been widely used in an attempt to identify common genetic variations that carry a mild to moderately increased risk to develop a disease. Over the years, literally hundreds of studies have been published, but unfortunately, only very few of them have produced robust and reproducible results. Several are the reasons which can justify the failure of this approach: most studies were greatly underpowered in relation to the small increases in the relative risk that today are known to be conferred by common genetic variants (usually the odds ratios are in the range of 1.2–2, with some exceptions, for example apolipoprotein E for AD). Then the choice of candidate genes was often based on rather arbitrary rationales with very weak experimental or epidemiologic evidence. As the gene-mapping studies in monogenic diseases have shown, newly identified genes most often could not have been predicted based on the current knowledge of pathogenesis. Furthermore in most studies only arbitrarily chosen individual genetic variants were investigated, thus it was a priori unlikely that the causative variant or a variant in high linkage disequilibrium, tagging the risk-conferring variant, would be among those studied. Finally, it is not easy to match patient and control cohorts with respect to their genetic background. Often, due to different recruiting strategies, these cohorts differ in their genetic composition (a problem called undetected population stratification, which today can be easily resolved in GWAS, see below). Due to different allele frequencies in different populations, spurious associations can be detected.

In the idiopatic cases an attempt is made to evaluate the PD population as a whole, using association studies and non parametric linkage methodology and trying to define risk alleles that contribute to the sporadic form of the disease.

mentioned recessive genes. Although the role of heterozygous mutations in the development of clinical signs currently remains a matter for debate, there is growing evidence that they are associated with pre clinical changes. PET studies have revealed reduced [18F]fluoro-dopa uptake by nerve terminals in the striatum of heterozygotes; there are also structural neuroimaging changes that indicate an increased deposition of metals in the substantia nigra, and there is reorganization of striatocortical motor loops with detectable changes in connectivity patterns.These collective data have important implications. Some carriers of heterozygous mutations might be in the preclinical period of PD, thereby affording unique opportunities to examine the relative risk associated with the affected allele and to study the natural history of the disease. This group also represents an ideal study population to be used not only to investigate compensatory mechanisms, facilitating the development of a sensitive surrogate marker, but also to detect the earliest PD-specific changes, allowing the development of urgently needed clinical biomarkers. Finally, these individuals could provide a small, but important, target population in which to evaluate the 'proof of principle' of a therapeutic intervention in future neuroprotection

Sporadic PD is multifactorial, complex and polygenic, generally determined by several common non-coding genetic variants, each of them play a role as a very modest risk factor singularly but with an important cumulative effect taken all together, interacting with environmental factors, other genes or functional variants, controlling the expression, splicing, phosphorylation, influencing the age at onset, severity and progression of the syndrome. Association studies have been widely used in an attempt to identify common genetic variations that carry a mild to moderately increased risk to develop a disease. Over the years, literally hundreds of studies have been published, but unfortunately, only very few of them have produced robust and reproducible results. Several are the reasons which can justify the failure of this approach: most studies were greatly underpowered in relation to the small increases in the relative risk that today are known to be conferred by common genetic variants (usually the odds ratios are in the range of 1.2–2, with some exceptions, for example apolipoprotein E for AD). Then the choice of candidate genes was often based on rather arbitrary rationales with very weak experimental or epidemiologic evidence. As the gene-mapping studies in monogenic diseases have shown, newly identified genes most often could not have been predicted based on the current knowledge of pathogenesis. Furthermore in most studies only arbitrarily chosen individual genetic variants were investigated, thus it was a priori unlikely that the causative variant or a variant in high linkage disequilibrium, tagging the risk-conferring variant, would be among those studied. Finally, it is not easy to match patient and control cohorts with respect to their genetic background. Often, due to different recruiting strategies, these cohorts differ in their genetic composition (a problem called undetected population stratification, which today can be easily resolved in GWAS, see below). Due to different allele frequencies in different

In the idiopatic cases an attempt is made to evaluate the PD population as a whole, using association studies and non parametric linkage methodology and trying to define risk alleles

trials.

**6. Sporadic PD** 

populations, spurious associations can be detected.

that contribute to the sporadic form of the disease.

Common genetic variants in *SNCA* can increase the susceptibility for idiopatic PD, while the *LRRK2* p.G2019S mutation can cause sporadic PD. Recently GWAS discovered new genes associated with PD: *GBA*, *MAPT*, *GAK, BST1, HLA, LONGO1*and *LONGO2, PARK16, SYNPHILIN.* 

#### **6.1 SNCA (PARK1-4, 4q21)**

Previous studies have found associations between Parkinson's disease and polymorphisms located within both the α-synuclein gene promoter and other gene regions. Particularly interesting is a complex polymorphic dinucleotide repeat polymorphism (NACP-REP1), located 10 kb upstream of the transcriptional start site of *SNCA*. In this case the number of dinucleotide repeats are directly linked to an higher risk to develop PD. Indeed the 263 haplotype is associated to the disease while the 259 one has a protective effect.

The *SNCA* gene consists in two haplotype blocks (genetic regions usually inherited as a single block, with a high degree of Linkage disequilibrium). The first block ranges from the promoter region to intron 4 while the second block includes exons 5 and 6 and the 3' untraslated region. The second block gives the strongest association signal with PD. Becasuse the SNP variability is noncoding and not within a region of species-conserved sequence identity or a miRNA binding site, the biologic mechanism remain unclear. Alternative splicing, phosporilation, expression modification or even linkage disequilibrium with another functional variant within the gene have been hypothesized as possible mechanisms. Gene expression may also be influenced by epigenetic interactions, including methylation, recently implicated in the downregulation of *SNCA* gene expression, which may warrant further investigation.

#### **6.2 LRRK2 (PARK8,12q12)**

Even if mutation in *LRRK2* are the most common cause of familial autosomal dominant PD, the p.G2019S substitution is of special significance as it is frequently identified not only in autosomal dominant, but also sporadic PD. Thus, being the most common cause of PD. The mutation is particularly frequent in PD patients residing in, or having genealogical ties to North Africa or the Middle East. This phenomenon can be explained by the fact that most *LRRK2* p.G2019S substitution carriers originate from a common founder.

#### **6.2.1 The LRRK2 c.6055G>A (p.G2019S) mutation**

P.G2019S is located in the mitogen-activated protein kinase (MAP) domain of the LRRK2 protein. The identification of p.G2019S substitutions as the most common cause of both familial and sporadic PD has been a major breakthrough. The frequency of p.G2019S substitutions differ remarkably throughout the world. This is due to a common founder for most p.G2019S carriers, originating from the Middle East or North Africa. Two large studies on Lrrk2 p.G2019S parkinsonism conclude that the phenotype of Lrrk2 p.G2019S can not be distinguished from idiopathic PD. There are some indications of a more benign course of p.G2019S parkinsonism compared to idiopathic PD with a slower disease progression and less cognitive impairment. However, methodological issues may have contributed to these observations. The penetrance of Lrrk2 p.G2019S has been much debated over the last years. Hulihan et al. investigated sporadic PD in Tunisia and found a lifetime penetrance of 45% (95% CI: 20–100%) for p.G2019S substitution carriers. Healy et al. additionally included hereditary patients and estimated that 74% had PD by age 79 years. Interestingly,

proposed of a possible cause of selective vulnerability of dopaminergic neurons in PD. Associated SNPs in the *BST1* region may modify ADP-ribosylcyclase activity, thus leading

The *HLA* variant that displayed the strongest statistical association with Parkinson's disease, rs3129882, is a noncoding polymorphism in intron 1 of *HLA-DRA*. The protein chains encoded by the closely linked *HLA-DRA* and *HLA-DRB* form the class II HLA-DR antigens that are expressed by antigen-presenting cells, including microglia in the brain, and which interact with T-cell receptors. HLA-DRB chains are highly variable and have been associated with numerous disorders, including multiple sclerosis, which, like Parkinson's disease, is a progressive neurodegenerative disorder. HLA-DRA, on the other hand, is practically monomorphic and therefore has not been investigated for disease association. The conventional explanation for this finding is that PD is associated with a classical polymorphic HLA antigen and that rs3129882 is a proxy for this antigen. Alternatively, the association of Parkinson's disease with an intronic *DRA* variant may reflect involvement of regulatory elements, which would be in line with Parkinson's disease–specific overexpression of DR antigens in substantia nigra. The evidence for genetic association of PD with HLA region, particularly when obtained from a hypothesis free-GWAS, where the entire genome is scanned without pre-existing bias towards any particular genes, lends strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson's disease pathogenesis. Studies have shown elevated DR expression in the brain and cerebrospinal fluid of individual with PD. The sustained presence of reactive DR positive microglia has been observed in the substantia nigra of individuals with PD, as well as animals and humans affected with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropiridine-induced (MPTP) parkinsonism. It is postulated that chronic immune activation and neuroinflammation occurs in response to an initial trigger, possibly related to alpha-synuclein accumulation, and produces neurotoxins and oxidative damage that could kill neurons. From a therapeutic perspective, vaccination aimed neutralizing neuroimmune dysfunction was recently shown to attenuate neurodegeneration in a Parkinson's disease model: further, NSAID use is associated with reduced reduced risk of developing PD in humans. The newly discovered association of PD with HLA region highlights the involvement of an important biological pathway in the etiology of the disease and point to a potential drug target that will stimulate research toward

A significant overlap between the diagnoses of PD and essential tremor (ET) is frequently observed. In retrospective analyses, 6-20% of ET patients have been described to exhibit signs of Parkinsonism. A recent prospective study demonstrated that patients with ET have a four-fold elevated risk to develop PD over an observational period of 3.3 years. Conversely, a diagnosis of ET was proposed to be 5 to 10 times more likely in subjects with PD than in controls. Furthermore it has been demonstrated that the risk of ET in first-degree relatives of patients with PD is significantly elevated. A neuropatholgical study demonstrated the occurrence of Lewy bodies in the brainstem in an older subset of ET patients. Genetic variation in the leucine-rich repeat and Ig domain containing Nogo receptor interacting protein1, (LINGO1) and its paralog (LINGO2) was recently associated

to Ca2+ dyshomeostasis in dopaminergic neurons.

**6.7 HLA (HLA-DRA; HLA-DQ;HLA-DR (6p21.3)** 

new therapies.

**6.8 LINGO1 and LINGO2 (15q24.3)(9p21.2)**

homozygous p.G2019S carriers do not have more severe disease than heterozygous carriers, this lack of gene-dose effect is consistent with the hypothesis that the p.G2019S substitution increases kinase activity. The pathology of p.G2019S parkinsonism is consistent with LBD in most, but not all cases.

#### **6.3 GBA (1q21)**

*GBA* is responsible to cause Gaucher Disease, GD, when the mutation is present in homozigosity. Patients with GD and relatives have an increased susceptibility for PD (2-3 fold), susceptibility which can increase among different populations like Ashkenazi Jews (5- 6 fold), when the mutation in the gene is present in heterozigosity. *GBA* encodes a lysosomal enzyme that cleaves glucocerebroside. As α-synuclein is in part degraded by chaperonemediated lysosomal pathway, it is conceivable that *GBA* mutations may increase the risk for PD by altering cellular α-synuclein homeostasis. It is supposed that the pathologic effect is due to the lack of the physiologic function or gain of a toxic one. Neuropathologically, Lewy bodies are present in the hippocampal region, corresponding to Braak stages 5 and 6, indicating that the dementia can be very similar to Lewy bodies dementia. Phenotipically GBA mutations carriers present the clinical features of sporadic PD with an higher and more severe incidence of dementia, olphactory disfunction, bradikinesia and a lower frequency of rigidity.

#### **6.4 MAPT (17q21.1)**

*MAPT*, encodes for the microtubule associated protein tau. Risk alleles of the associated SNPs are in LD with the H1 haplotype. An association between *MAPT* locus and PD could seem surprising, given the classic separation of synucleinopathies and tauopathies but the role of *MAPT* in neurodegenerative diseases is well established and this association is biologically plausible, despite the lack of neuropathology in PD. The combination of risk variants in *MAPT* and *SNCA* doubles the risk of developing PD, supporting the idea that related pathways contribute to neurodegenerative diseases. Finally, although we do not understand the relationship between the *MAPT* locus and Parkinson disease, it is worth remembering that while *LRRK2* mutations usually give rise to a-synuclein pathology, they sometimes give rise to tangle pathology (Zimprich et al., 2004) and that, while *MAPT* mutations usually give rise to tangle pathology, they sometimes give rise to Lewy body pathology.

An association to *MAPT* is absent in the Asian population.

#### **6.5 GAK (4p16)**

*GAK* (cyclin G associated kinase, a cell cycle regulator) is a serine thereonine kinase. It is a particularly promising candidate because it is one of 137 genes shown to be differentially espressed in PD, with an 1.56 fold change in expression in the substantia nigra pars compacta of PD patients compared to controls. Protective role postulated: decreased in expression or depletion enhance alpha-synuclein toxicity.

#### **6.6 BST1 (4p15)**

*BST1*(bone marrow stromal cell antigen) catalyses the formation of cyclic ADP-ribose (cADPR). cADPR mobilizes calcium (Ca2+) from ryanodine sensitive intracellular Ca2+, stored in the endoplasmic reticulum. Distruption of the Ca2+ homeostasis has recently been

homozygous p.G2019S carriers do not have more severe disease than heterozygous carriers, this lack of gene-dose effect is consistent with the hypothesis that the p.G2019S substitution increases kinase activity. The pathology of p.G2019S parkinsonism is consistent with LBD in

*GBA* is responsible to cause Gaucher Disease, GD, when the mutation is present in homozigosity. Patients with GD and relatives have an increased susceptibility for PD (2-3 fold), susceptibility which can increase among different populations like Ashkenazi Jews (5- 6 fold), when the mutation in the gene is present in heterozigosity. *GBA* encodes a lysosomal enzyme that cleaves glucocerebroside. As α-synuclein is in part degraded by chaperonemediated lysosomal pathway, it is conceivable that *GBA* mutations may increase the risk for PD by altering cellular α-synuclein homeostasis. It is supposed that the pathologic effect is due to the lack of the physiologic function or gain of a toxic one. Neuropathologically, Lewy bodies are present in the hippocampal region, corresponding to Braak stages 5 and 6, indicating that the dementia can be very similar to Lewy bodies dementia. Phenotipically GBA mutations carriers present the clinical features of sporadic PD with an higher and more severe incidence of dementia, olphactory disfunction, bradikinesia and a lower frequency of

*MAPT*, encodes for the microtubule associated protein tau. Risk alleles of the associated SNPs are in LD with the H1 haplotype. An association between *MAPT* locus and PD could seem surprising, given the classic separation of synucleinopathies and tauopathies but the role of *MAPT* in neurodegenerative diseases is well established and this association is biologically plausible, despite the lack of neuropathology in PD. The combination of risk variants in *MAPT* and *SNCA* doubles the risk of developing PD, supporting the idea that related pathways contribute to neurodegenerative diseases. Finally, although we do not understand the relationship between the *MAPT* locus and Parkinson disease, it is worth remembering that while *LRRK2* mutations usually give rise to a-synuclein pathology, they sometimes give rise to tangle pathology (Zimprich et al., 2004) and that, while *MAPT* mutations usually give rise to tangle pathology, they sometimes give rise to Lewy body

*GAK* (cyclin G associated kinase, a cell cycle regulator) is a serine thereonine kinase. It is a particularly promising candidate because it is one of 137 genes shown to be differentially espressed in PD, with an 1.56 fold change in expression in the substantia nigra pars compacta of PD patients compared to controls. Protective role postulated: decreased in

*BST1*(bone marrow stromal cell antigen) catalyses the formation of cyclic ADP-ribose (cADPR). cADPR mobilizes calcium (Ca2+) from ryanodine sensitive intracellular Ca2+, stored in the endoplasmic reticulum. Distruption of the Ca2+ homeostasis has recently been

An association to *MAPT* is absent in the Asian population.

expression or depletion enhance alpha-synuclein toxicity.

most, but not all cases.

**6.3 GBA (1q21)** 

rigidity.

pathology.

**6.5 GAK (4p16)** 

**6.6 BST1 (4p15)** 

**6.4 MAPT (17q21.1)** 

proposed of a possible cause of selective vulnerability of dopaminergic neurons in PD. Associated SNPs in the *BST1* region may modify ADP-ribosylcyclase activity, thus leading to Ca2+ dyshomeostasis in dopaminergic neurons.

#### **6.7 HLA (HLA-DRA; HLA-DQ;HLA-DR (6p21.3)**

The *HLA* variant that displayed the strongest statistical association with Parkinson's disease, rs3129882, is a noncoding polymorphism in intron 1 of *HLA-DRA*. The protein chains encoded by the closely linked *HLA-DRA* and *HLA-DRB* form the class II HLA-DR antigens that are expressed by antigen-presenting cells, including microglia in the brain, and which interact with T-cell receptors. HLA-DRB chains are highly variable and have been associated with numerous disorders, including multiple sclerosis, which, like Parkinson's disease, is a progressive neurodegenerative disorder. HLA-DRA, on the other hand, is practically monomorphic and therefore has not been investigated for disease association. The conventional explanation for this finding is that PD is associated with a classical polymorphic HLA antigen and that rs3129882 is a proxy for this antigen. Alternatively, the association of Parkinson's disease with an intronic *DRA* variant may reflect involvement of regulatory elements, which would be in line with Parkinson's disease–specific overexpression of DR antigens in substantia nigra. The evidence for genetic association of PD with HLA region, particularly when obtained from a hypothesis free-GWAS, where the entire genome is scanned without pre-existing bias towards any particular genes, lends strong and independent support to the involvement of neuroinflammation and humoral immunity in Parkinson's disease pathogenesis. Studies have shown elevated DR expression in the brain and cerebrospinal fluid of individual with PD. The sustained presence of reactive DR positive microglia has been observed in the substantia nigra of individuals with PD, as well as animals and humans affected with 1-methyl-4-phenyl-1,2,3,6,-tetrahydropiridine-induced (MPTP) parkinsonism. It is postulated that chronic immune activation and neuroinflammation occurs in response to an initial trigger, possibly related to alpha-synuclein accumulation, and produces neurotoxins and oxidative damage that could kill neurons. From a therapeutic perspective, vaccination aimed neutralizing neuroimmune dysfunction was recently shown to attenuate neurodegeneration in a Parkinson's disease model: further, NSAID use is associated with reduced reduced risk of developing PD in humans. The newly discovered association of PD with HLA region highlights the involvement of an important biological pathway in the etiology of the disease and point to a potential drug target that will stimulate research toward new therapies.

#### **6.8 LINGO1 and LINGO2 (15q24.3)(9p21.2)**

A significant overlap between the diagnoses of PD and essential tremor (ET) is frequently observed. In retrospective analyses, 6-20% of ET patients have been described to exhibit signs of Parkinsonism. A recent prospective study demonstrated that patients with ET have a four-fold elevated risk to develop PD over an observational period of 3.3 years. Conversely, a diagnosis of ET was proposed to be 5 to 10 times more likely in subjects with PD than in controls. Furthermore it has been demonstrated that the risk of ET in first-degree relatives of patients with PD is significantly elevated. A neuropatholgical study demonstrated the occurrence of Lewy bodies in the brainstem in an older subset of ET patients. Genetic variation in the leucine-rich repeat and Ig domain containing Nogo receptor interacting protein1, (LINGO1) and its paralog (LINGO2) was recently associated

Familial and sporadic PD present similar clinical features, which reinforce the hypothesis that common pathways might be at the basis of a so analogous phenotype. Generally dystonia appears as the first symptom in the familial cases, while gait impairment and postural instability are one of the first manifestation for the sporadic ones. Evidence is emerging that some of the pathways covered in the rare monogenic forms of PD: dysfunction or impairment of the ubiquitin-proteosome system and/or mytochondria, may play a direct role in the etiology of the common sporadic disorder and genetic variation

So far, the proteins that have been linked to parkinsonism by genetic studies have roles

• mitochondrial function (α-synuclein, *PARKIN*, *PINK1*, *DJ-1*, *FBXO7*, *Omi/HtrA2*,

• embryonic development (α-synuclein, *PARKIN*, *UCHL1*, *LRRK2*, *Omi/HtrA2*, *NURR1*,

These disparate functions might overlap as they all lead to the age-associated dysfunction and death of dopaminergic neurons that characterize PD. However, the relationships between these functions are not direct and the connections between them are not

**7.1 Mitochondrial dysfunction (α-synuclein,** *PARKIN***,** *PINK1***,** *DJ-1***,** *FBXO7***,** *POLG1,* 

The pathway that has come most clearly out of the analysis of the Mendelian genes is a mitochondrial damage repair pathway. α*-*synuclein has long been known to modulate mitochondrial function, but the mechanism remains unknown. A possible role in mitochondrial signaling has been hypothesized. Parkin enhances transcription and replication of mitochondrial DNA in proliferating cells. Furthermore, Parkin, an E3 ubiquitin ligase, and PINK1, a mitochondrial kinase, are involved in the elimination of damaged mitochondria. DJ-1, and possibly FBX07, another ubiquitin ligase, are also likely to play a role in the mitochondrial pathway. DJ-1 can protect the cell against oxidative stress and can also translocate to the mitochondria. (Cookson 2010). The similar phenotype can confirm a common role of these genes in the mitochondrial pathway (Paisan-Ruiz et al.,

POLG1 is a mitochondrial DNA polymerase (Polymerase gamma 1) of the inner membrane that synthesizes, replicates and repairs mitochondrial DNA. Several mutations within POLG1 have been associated with parkinsonism in addition to other clinical

HtrA2 also known as Omi (HtrA2/Omi) is serine protease localized to the inner membrane space of mitochondria. A variation within Omi (G399S) was found in four patients with late-

**7. Pathogenic pathways** 

in:

*POLG1*)

• oxidative stress

immediately evident.

*PITX3*)

*Omi/HtrA2***)** 

phenotypes.

contribute to the risk of developing PD.

• the ubiquitin–proteosome system (*PARKIN* and *UCHL1*)

• lysosome (*GBA*, *ATP13A2*)

• vescicle dynamics (α-synuclein), • MAPKKK signaling (*LRRK2*),

• microtubule stability (*MAPT*)

2010; Valente et al., 2004;Yamamura 2010).

with an increased risk of developing essential tremor (ET) and Parkinson's disease (PD). LINGO1 plays a role in early brain development and oligodendrocyte differentiation. Because of its presumed role in neural survival and myelination, LINGO1 has been targeted in vivo and in vitro in model of spinal cord injury, autoimmune encephalitis and PD.

#### **6.9 PARK16(1q32)**

The PARK16 region contains five functionally interesting candidate genes for PD etiology. *SLC41A1* is a magnesium (Mg2+) transporter. It is of interest that Mg2+ deficiency is thought to be an environmental risk factor for the amyotrophic lateral sclerosis (ALS) parkinsonism/dementia complex. Furthermore, *RAB7L1* is a small GTP-binding protein that plays an important role in regulation of exo-and endocytotic pathways, and *NUCKS1* is a nuclear protein containing several consensus phosphorylation sites for casein kinase II and cyclin-dependent kinases of unknown function.

Although pathogenic mutations and risk alleles within the PARK16 locus seem to be rare in European ancestry populations, further molecular analyses within different populations are required to examine its biochemical role in PD.

#### **6.10 Synphilin**

The presynaptic protein synphilin 1 and its isoform 1A have been associated with PD. Synphilin is an interactor of α-synuclein and is modulated by parkin. Synphilin is widely expressed with highest levels in brain, heart and placenta.

#### **6.11 Omi/HtrA2 (PARK 13, 2p12)**

*In vitro* and *in vivo* studies strongly implicate loss of Omi/HtrA2 protein in disrupted mitochondrial homeostasis and subsequent cell death. Moreover, recent pathoanatomical studies indicate that Omi/HtrA2 represents a consistent pathological marker for neurodegeneration in different α-synucleinopathies (Kawamoto et al.,2008). Loss of Omi/HtrA2 function may contribute to a broader spectrum of neurodegeneration, as decreased levels of Omi/HtrA2 were demonstrated in brains of Huntington's disease patients. Therefore, while some genetic association studies provide no consistent support for an association of *Omi/HtrA2* and PD, functional studies suggest that further study of this gene in the context of neurodegenerative disorders is justified. We cannot exclude the possibility that other neurodegenerative diseases besides PD may be influenced by *Omi/HtrA2* variations.

Recent discoveries from meta-analysis study of previous GWAS, identified 11 loci that surpassed the threshold for genome-wide significance (p<5x10(-8)). Six were already known loci (*MAPT*, *SNCA*, *HLA-DRB5*, *BST1*, *GAK* and *LRRK2*) and 5 were newly identified loci (*ACMSD*, *STK39*, *MCCC1/LAMP3*, *SYT11* and *CCDC62/HIP1R*) (International Parkinson's Disease Genomic Consortium, 2011)

*ACMSD* is involved in picolinic and quinolinic acid homoeostasis and is a possible therapeutic target for several disorders that affect the CNS. The locus identified near *STK39*  has been associated with autism and infl ammatory status, although there have been no reports of this locus contributing to neurodegenerative phenotypes. The *LAMP3* locus might modulate neurosecretory function in PC12 cell lines.

*HLA-DRB5* is involved in multiple sclerosis, immunocompetence, and histocompatibility. The association with Parkinson's disease at *HLA-DRB5* supports the theory that inflammatory factors are associated with the pathogenesis of PD.

with an increased risk of developing essential tremor (ET) and Parkinson's disease (PD). LINGO1 plays a role in early brain development and oligodendrocyte differentiation. Because of its presumed role in neural survival and myelination, LINGO1 has been targeted

The PARK16 region contains five functionally interesting candidate genes for PD etiology. *SLC41A1* is a magnesium (Mg2+) transporter. It is of interest that Mg2+ deficiency is thought to be an environmental risk factor for the amyotrophic lateral sclerosis (ALS) parkinsonism/dementia complex. Furthermore, *RAB7L1* is a small GTP-binding protein that plays an important role in regulation of exo-and endocytotic pathways, and *NUCKS1* is a nuclear protein containing several consensus phosphorylation sites for casein kinase II and

Although pathogenic mutations and risk alleles within the PARK16 locus seem to be rare in European ancestry populations, further molecular analyses within different populations are

The presynaptic protein synphilin 1 and its isoform 1A have been associated with PD. Synphilin is an interactor of α-synuclein and is modulated by parkin. Synphilin is widely

*In vitro* and *in vivo* studies strongly implicate loss of Omi/HtrA2 protein in disrupted mitochondrial homeostasis and subsequent cell death. Moreover, recent pathoanatomical studies indicate that Omi/HtrA2 represents a consistent pathological marker for neurodegeneration in different α-synucleinopathies (Kawamoto et al.,2008). Loss of Omi/HtrA2 function may contribute to a broader spectrum of neurodegeneration, as decreased levels of Omi/HtrA2 were demonstrated in brains of Huntington's disease patients. Therefore, while some genetic association studies provide no consistent support for an association of *Omi/HtrA2* and PD, functional studies suggest that further study of this gene in the context of neurodegenerative disorders is justified. We cannot exclude the possibility that other neurodegenerative diseases besides PD may be influenced by *Omi/HtrA2* variations. Recent discoveries from meta-analysis study of previous GWAS, identified 11 loci that surpassed the threshold for genome-wide significance (p<5x10(-8)). Six were already known loci (*MAPT*, *SNCA*, *HLA-DRB5*, *BST1*, *GAK* and *LRRK2*) and 5 were newly identified loci (*ACMSD*, *STK39*, *MCCC1/LAMP3*, *SYT11* and *CCDC62/HIP1R*) (International Parkinson's

*ACMSD* is involved in picolinic and quinolinic acid homoeostasis and is a possible therapeutic target for several disorders that affect the CNS. The locus identified near *STK39*  has been associated with autism and infl ammatory status, although there have been no reports of this locus contributing to neurodegenerative phenotypes. The *LAMP3* locus might

*HLA-DRB5* is involved in multiple sclerosis, immunocompetence, and histocompatibility. The association with Parkinson's disease at *HLA-DRB5* supports the theory that

in vivo and in vitro in model of spinal cord injury, autoimmune encephalitis and PD.

**6.9 PARK16(1q32)** 

**6.10 Synphilin** 

cyclin-dependent kinases of unknown function.

required to examine its biochemical role in PD.

**6.11 Omi/HtrA2 (PARK 13, 2p12)** 

Disease Genomic Consortium, 2011)

modulate neurosecretory function in PC12 cell lines.

inflammatory factors are associated with the pathogenesis of PD.

expressed with highest levels in brain, heart and placenta.
