**9. References**


Fung, H. C., Scholz, S., Matarin, M., Simon-Sanchez, J., Hernandez, D., Britton, A., et al.

Gasser, T. (2008). Hunting for genes and mutations: It's worth remembering the basics.

Gasser, T. (2009a). Mendelian forms of Parkinson's disease. Biochimica et Biophysica Acta,

Gasser, T. (2009b). Molecular pathogenesis of Parkinson disease: Insights from genetic

Gilks, W. P., Abou-Sleiman, P. M., Gandhi, S., Jain, S., Singleton, A., Lees, A. J., et al. (2005).

Gloeckner, C. J., Kinkl, N., Schumacher, A., Braun, R. J., O'Neill, E., Meitinger, T., et al.

Goedert, M., Spillantini, M. G., & Davies, S. W. (1998). Filamentous nerve cell inclusions in neurodegenerative diseases. Current Opinion Neurobiology, 8(5), 619–632. Goedert, M., Wischik, C. M., Crowther, R. A., Walker, J. E., & Klug, A. (1988). Cloning and

Goker-Alpan, O., Giasson, B. I., Eblan, M. J., Nguyen, J., Hurtig, H. I., Lee, V. M., et al.

Golbe, L. I., Di Iorio, G., Bonavita, V., Miller, D. C., & Duvoisin, R. C. (1990). A large kindred

Goldwurm, S., Di Fonzo, A., Simons, E. J., Rohe, C. F., Zini, M., Canesi, M., et al. (2005). The

Goris, A., Williams-Gray, C. H., Clark, G. R., Foltynie, T., Lewis, S. J., Brown, J., et al. (2007).

Grabowski, G. A. (2008). Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet,

Harbo, H. F., Finsterer, J., Baets, J., Van Broeckhoven, C., Di Donato, S., Fontaine, B., et al.

increased kinase activity. Human Molecular Genetics, 15(2), 223–232. Goate, A., Chartier-Harlin, M. C., Mullan, M., Brown, J., Crawford, F., Fidani, L., et al.

with familial Alzheimer's disease. Nature, 349(6311), 704–706

A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet, 365(9457),

(2006). The Parkinson disease causing LRRK2 mutation I2020T is associated with

(1991). Segregation of a missense mutation in the amyloid precursor protein gene

sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proceedings of the National Academy of Sciences of the United States of America,

(2006). Glucocerebrosidase mutations are an important risk factor for Lewy body

with autosomal dominant Parkinson's disease. Annals of Neurology, 27(3), 276–

G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. Journal of Medical

Tau and alpha-synuclein in susceptibility to, and dementia in, Parkinson's disease.

(2009). EFNS guidelines on the molecular diagnosis of neurogenetic disorders: General issues, Huntington's disease, Parkinson's disease and dystonias. European

studies. Expert Reviews in Molecular Medicine, 11, e22.

911–916.

415–416.

1792(7), 587–596.

85(11), 4051–4055.

Genetics, 42(11), e65.

372(9645), 1263–1271.

282.

disorders. Neurology, 67(5), 908–910.

Annals of Neurology, 62(2), 145–153.

Journal of Neurology, 16(7), 777–785.

Neurology, 70(16 Pt 2), 1373–1374.

(2006). Genome-wide genotyping in Parkinson's disease and neurologically normal controls: First stage analysis and public release of data. Lancet Neurology, 5(11),


Cookson, M. R., & van der Brug, M. (2007). Cell systems and the toxic mechanism(s) of

Dehghan, A., Kottgen, A., Yang, Q., Hwang, S. J., Kao, W. L., Rivadeneira, F., et al. (2008).

De Marco, E. V., Annesi, G., Tarantino, P., Rocca, F. E., Provenzano, G., Civitelli, D., et al.

Denson, M. A., & Wszolek, Z. K. (1995). Familial parkinsonism: Our experience and a review

Derkatch, I. L., Uptain, S. M., Outeiro, T. F., Krishnan, R., Lindquist, S. L., & Liebman, S. W.

Dickson, D. W., Lin, W., Liu, W. K., & Yen, S. H. (1999). Multiple system atrophy: A sporadic

Di Fonzo, A., Rohe, C. F., Ferreira, J., Chien, H. F., Vacca, L., Stocchi, F., et al. (2005). A

Dodson, M. W., & Guo, M. (2007). Pink1, Parkin, DJ-1 and mitochondrial dysfunction in Parkinson's disease. Current Opinion in Neurobiology, 17(3), 331–337. Duda, J. E., Giasson, B. I., Mabon, M. E., Miller, D. C., Golbe, L. I., Lee, V. M., et al. (2002).

Elstner, M., Morris, C. M., Heim, K., Lichtner, P., Bender, A., Mehta, D., et al. (2009). Single-

Farrer, M., Gwinn, K., Muenter, M., DeVrieze, F. W., Crook, R., Perez Tur, J., et al. (1999). 4p

Farrer, M. J., Stone, J. T., Lin, C. H., Dachsel, J. C., Hulihan, M. M., Haugarvoll, K., et al.

Fuchs, J., Nilsson, C., Kachergus, J., Munz, M., Larsson, E. M., Schule, B., et al. (2007).

Fuchs, J., Tichopad, A., Golub, Y., Munz, M., Schweitzer, K. J., Wolf, B., et al. (2008). Genetic

Funayama, M., Hasegawa, K., Kowa, H., Saito, M., Tsuji, S., & Obata, F. (2002). A new locus

Association of three genetic loci with uric acid concentration and risk of gout: A

(2008). Glucocerebrosidase gene mutations are associated with Parkinson's disease

(2004). Effects of Q/Nrich, polyQ, and non-polyQ amyloids on the de novo formation of the [PSIþ] prion in yeast and aggregation of Sup35 in vitro. Proceedings of the National Academy of Sciences of the United States of America,

frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's

Concurrence of alpha-synuclein and tau brain pathology in the Contursi kindred.

cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene. Annals of

haplotype segregating with familial Lewy body parkinsonism. Movement

(2007). Lrrk2 G2385R is an ancestral risk factor for Parkinson's disease in Asia.

Phenotypic variation in a large Swedish pedigree due to SNCA duplication and

variability in the SNCA gene influences alpha-synuclein levels in the blood and

for Parkinson's disease (PARK8) maps to chromosome 12p11.2-q13.1. Annals of

alpha-synuclein. Experimental Neurology, 290(1), 5–11.

in southern Italy. Movement Disorders, 23(3), 460–463.

synucleinopathy. Brain Pathology, 9(4), 721–732.

disease. Lancet, 365(9457), 412–415.

Neurology, 66(6), 792–798.

Neurology, 51(3), 296–301.

Disorders, 13 (Suppl. 2), 253–253.

Acta Neuropathologica (Berl), 104(1), 7–11.

Parkinsonism & Related Disorders, 13(2), 89–92.

triplication. Neurology, 68(12), 916–922.

brain. The FASEB Journal, 22(5), 1327–1334.

101(35), 12934–12939.

genomewide association study. Lancet, 372(9654), 1953–1961.

of the literature. Parkinsonism & Related Disorders, 1(1), 35–46.


Kwok, J. B., Teber, E. T., Loy, C., Hallupp, M., Nicholson, G., Mellick, G. D., et al. (2004). Tau

Latourelle, J. C., Pankratz, N., Dumitriu, A., Wilk, J. B., Goldwurm, S., Pezzoli, G., et al.

Lesage, S., Durr, A., Tazir, M., Lohmann, E., Leutenegger, A. L., Janin, S., et al. (2006).

Levy, S., Sutton, G., Ng, P. C., Feuk, L., Halpern, A. L., Walenz, B. P., et al. (2007). The diploid genome sequence of an individual human. PLoS Biology, 5(10), e254. Lu, C. S., Wu-Chou, Y. H., van Doeselaar, M., Simons, E. J., Chang, H. C., Breedveld, G. J., et

Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D. C., Nazareth, L., et

Neuropathy. The New England Journal of Medicine, 362(13), 1181– 1191. Lücking, C. B., Dürr, A., Bonifati, V., Vaughan, J., De Michele, G., Gasser, T., et al. (2000).

Machaczka, M., Rucinska, M., Skotnicki, A. B., & Jurczak, W. (1999). Parkinson's syndrome

Maraganore, D. M., de Andrade, M., Elbaz, A., Farrer, M. J., Ioannidis, J. P., Kruger, R., et al.

Maraganore, D. M., de Andrade, M., Lesnick, T. G., Strain, K. J., Farrer, M. J., Rocca, W. A.,

Martin, E. R., Scott, W. K., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., et al.

Mata, I. F., Samii, A., Schneer, S. H., Roberts, J. W., Griffith, A., Leis, B. C., et al. (2008).

Matsumine, H., Saito, M., Shimoda-Matsubayashi, S., Tanaka, H., Ishikawa, A., Nakagawa-

Metzker, M. L. (2009). Sequencing technologies – the next generation. Nature Reviews

Mizuta, I., Satake, W., Nakabayashi, Y., Ito, C., Suzuki, S., Momose, Y., et al. (2006). Multiple

sporadic Parkinson's disease. Human Molecular Genetics, 15(7), 1151–1158.

Gene. The New England Journal of Medicine, 342(21), 1560-1567.

Annals of Neurology, 55(3), 329–334.

England Journal of Medicine, 354(4), 422–423.

the Chinese population. Neurogenetics, 9(4), 271–276.

Medical Genetics, 10, 98.

Hematology, 61(3), 216–217.

Parkinson disease. JAMA, 296(6), 661–670.

Archives of Neurology, 65(3), 379–382.

Genetics, 60(3), 588–596.

Genetics, 11(1), 31–46.

American Journal of Human Genetics, 77(5), 685–693.

Late-Onset Parkinson Disease. JAMA, 286(18), 2245–2250.

haplotypes regulate transcription and are associated with Parkinson's disease.

(2009). Genomewide association study for onset age in Parkinson disease. BMC

LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. The New

al. (2008). The LRRK2 Arg1628Pro variant is a risk factor for Parkinson's disease in

al. (2010). Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth

Association between Early-OnsetnParkinson's Disease and Mutations in the Parkin

preceding clinical manifestation of Gaucher's disease. American Journal of

(2006). Collaborative analysis of alpha-synuclein gene promoter variability and

et al. (2005). Highresolution whole-genome association study of Parkinson disease.

(2001). Association of Single Nucleotide Polymorphisms of the Tau Gene With

Glucocerebrosidase gene mutations: A risk factor for Lewy body disorders.

Hattori, Y., et al. (1997). Localization of a gene for an autosomal recessive form of juvenile Parkinsonism to chromosome 6q25.2-27. American Journal of Human

candidate gene analysis identifies {alpha}-synuclein as a susceptibility gene for


Hatano, Y., Li, Y., Sato, K., Asakawa, S., Yamamura, Y., Tomiyama, H., et al. (2004). Novel

Healy, D. G., Abou-Sleiman, P. M., Valente, E. M., Gilks, W. P., Bhatia, K., Quinn, N., et al.

Healy, D. G., Falchi, M., O'Sullivan, S. S., Bonifati, V., Durr, A., Bressman, S., et al. (2008).

Parkinson's disease: A case-control study. Lancet Neurology, 7(7), 583–590. Hedrich, K., Djarmati, A., Schafer, N., Hering, R., Wellenbrock, C., Weiss, P. H., et al. (2004).

Hering, R., Strauss, K. M., Tao, X., Bauer, A., Woitalla, D., Mietz, E. M., et al. (2004). Novel

Hutton, M., Lendon, C. L., Rizzu, P., Baker, M., Froelich, S., Houlden, H., et al. (1998).

Ibanez, P., Lesage, S., Janin, S., Lohmann, E., Durif, F., Destee, A., et al. (2009). Alpha-

International Parkinson's Disease Genomic Consortium (2011). Imputations of sequence

Ishikawa, A., & Tsuji, S. (1996). Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology, 47(1), 160–166. Kachergus, J., Mata, I. F., Hulihan, M., Taylor, J. P., Lincoln, S., Aasly, J., et al. (2005).

Karpinar, D. P., Balija, M. B., Kugler, S., Opazo, F., Rezaei-Ghaleh, N., Wender, N., et al.

Kitada, T., Asakawa, S., Hattori, N., Matsumine, H., Yamamura, Y., Minoshima, S., et al.

Klein, C., Schneider, S. A., & Lang, A. E. (2009). Hereditary parkinsonism: Parkinson disease

Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Ko¨ sel, S., et al. (1998). Ala30Pro

genome-wide association studies. Lancet, 377 (9766): 641-9.

American Journal of Human Genetics, 76(4), 672–680.

parkinsonism. Nature, 392, 605–608.

Disorders, 24(14), 2042–2058.

18, 106–108.

onset Parkinson disease. Neurology, 62(3), 389–394.

dementia FTDP-17. Nature, 393(6686), 702–705.

human genome. Nature, 431(7011), 931–945.

427.

and Psychiatry, 75(1), 144–145.

Human Mutation, 24(4), 321–329.

PINK1 mutations in early-onset parkinsonism. Annals of Neurology, 56(3), 424–

(2004). DJ-1 mutations in Parkinson's disease. Journal of Neurology, Neurosurgery,

Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated

DJ-1 (PARK7) mutations are less frequent than Parkin (PARK2) mutations in early-

homozygous p.E64D mutation in DJ1 in early onset Parkinson disease (PARK7).

Association of missense and 50splice-site mutations in tau with the inherited

synuclein gene rearrangements in dominantly inherited parkinsonism: Frequency, phenotype, and mechanisms. Archives of Neurology, 66(1), 102–108. International Human Genome Sequencing, C. (2004). Finishing the euchromatic sequence of the

variants for identification of genetic risk for Parkinson's disease: a meta-analysis of

Identification of a Novel LRRK2 Mutation Linked to Autosomal Dominant Parkinsonism: Evidence of a Common Founder across European Populations.

(2009). Pre-fibrillar alphasynuclein variants with impaired beta-structure increase neurotoxicity in Parkinson's disease models. The EMBO Journal, 28(20), 3256–3268.

(1998). Mutations in the parkin gene cause autosomal recessive juvenile

look-alikes–an algorithm for clinicians to 'PARK' genes and beyond. Movement

mutation in the gene encoding a-synuclein in Parkinson's disease. Nature Genetics,


Simon-Sanchez, J., Schulte, C., Bras, J. M., Sharma, M., Gibbs, J. R., Berg, D., et al. (2009).

Singleton, A. B., Farrer, M., Johnson, J., Singleton, A., Hague, S., Kachergus, J., et al. (2003).

Skipper, L., Wilkes, K., Toft, M., Baker, M., Lincoln, S., Hulihan, M., et al. (2004). Linkage

Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., & Goedert, M. (1997). Alpha-synuclein in Lewy bodies. Nature, 388(6645), 839–840. Spira, P. J., Sharpe, D. M., Halliday, G., Cavanagh, J., & Nicholson, G. A. (2001). Clinical and

Tayebi, N., Callahan, M., Madike, V., Stubblefield, B. K., Orvisky, E., Krasnewich, D., et al.

Valente, E. M., Abou-Sleiman, P. M., Caputo, V., Muqit, M. M., Harvey, K., Gispert, S., et al.

Valente, E. M., Bentivoglio, A. R., Dixon, P. H., Ferraris, A., Ialongo, T., Frontali, M., et al.

Valente, E. M., Salvi, S., Ialongo, T., Marongiu, R., Elia, A. E., Caputo, V., et al. (2004). PINK1

Wheeler, D. A., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., et al. (2008).

Williams, D. R. (2006). Tauopathies: Classification and clinical update on neurodegenerative

Winkler, S., Hagenah, J., Lincoln, S., Heckman, M., Haugarvoll, K., Lohmann-Hedrich, K., et

Zabetian, C. P., Hutter, C. M., Factor, S. A., Nutt, J. G., Higgins, D. S., Griffith, A., et al.

Zarranz, J. J., Alegre, J., Gomez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., et al. (2004).

Parkinson's disease. Annals of Neurology, 62(2), 137–144.

dementia. Annals of Neurology, 55(2), 164–173.

characterization. Molecular Genetics and Metabolism, 73(4), 313–321. Tobin, J. E., Latourelle, J. C., Lew, M. F., Klein, C., Suchowersky, O., Shill, H. A., et al. (2008).

alphasynuclein mutation. Annals of Neurology, 49(3), 313–319.

disease. Nature Genetics, 41(12), 1308–1312.

Journal of Human Genetics, 75(4), 669–677.

The GenePD Study. Neurology, 71(1), 28–34.

Science, 304(5674), 1158–1160.

Human Genetics, 68(4), 895–900.

Neurology, 56(3), 336–341.

Nature, 452(7189), 872–876.

Journal, 36 (10), 652–660.

1745–1750.

302(5646), 841.

Genome-wide association study reveals genetic risk underlying Parkinson's

{alpha}-Synuclein locus triplication causes Parkinson's DISEASE. Science,

disequilibrium and association of MAPT H1 in Parkinson disease. American

pathological features of a Parkinsonian syndrome in a family with an Ala53Thr

(2001). Gaucher disease and parkinsonism: A phenotypic and genotypic

Haplotypes and gene expression implicate the MAPT region for Parkinson disease:

(2004). Hereditary early-onset Parkinson's disease caused by mutations in PINK1.

(2001). Localization of a novel locus for autosomal recessive early-onset parkinsonism, park6, on human chromosome 1p35-p36. American Journal of

mutations are associated with sporadic early-onset parkinsonism. Annals of

The complete genome of an individual by massively parallel DNA sequencing.

diseases associated with microtubule-associated protein tau. Internal Medicine

al. (2007). Alpha-synuclein and Parkinson disease susceptibility. Neurology, 69(18),

(2007). Association analysis of MAPT H1 haplotype and subhaplotypes in

The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body


Mueller, J. C., Fuchs, J., Hofer, A., Zimprich, A., Lichtner, P., Illig, T., et al. (2005). Multiple

Neumann, J., Bras, J., Deas, E., O'Sullivan, S. S., Parkkinen, L., Lachmann, R. H., et al. (2009).

Ng, S.B., Buckingham, K.J., Lee, C., Bigham, A.W., Tabor, H.K., Dent, K.M., et al. (2010)

Nichols, W. C., Pankratz, N., Hernandez, D., Paisan-Ruiz, C., Jain, S., Halter, C. A., et al.

Ozelius, L. J., Senthil, G., Saunders-Pullman, R., Ohmann, E., Deligtisch, A., Tagliati, M., et

Paisan-Ruiz, C., Jain, S., Evans, E. W., Gilks, W. P., Simon, J., van der Brug, M., et al. (2004).

Pankratz, N., Wilk, J. B., Latourelle, J. C., DeStefano, A. L., Halter, C., Pugh, E. W., et al.

Pittman, A. M., Myers, A. J., Abou-Sleiman, P., Fung, H. C., Kaleem, M., Marlowe, L., et al.

Polymeropoulos, M. H., Higgins, J. J., Golbe, L. I., Johnson, W. G., Ide, S. E., Di Iorio, G., et

Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., et al. (1997).

Rogaeva, E., Johnson, J., Lang, A. E., Gulick, C., Gwinn- Hardy, K., Kawarai, T., et al. (2004).

Rohe, C. F., Montagna, P., Breedveld, G., Cortelli, P., Oostra, B. A., & Bonifati, V. (2004).

Satake, W., Nakabayashi, Y., Mizuta, I., Hirota, Y., Ito, C.,Kubo, M., et al. (2009). Genome-

Scott, W. K., Nance, M. A., Watts, R. L., Hubble, J. P., Koller, W. C., Lyons, K., et al. (2001).

factors for Parkinson's disease. Nature Genetics, 41(12), 1303–1307.

familial Parkinson disease. Human Genetics, 124(6), 593–605.

Neurology, 57 (4), 535–541.

42(1), 30–35.

disease. Brain, 132(Pt 7), 1783–1794.

disease. Neuron, 44(4), 595–600.

Science, 274, 1197–1199.

Science, 276, 2045–2047.

JAMA, 286(18), 2239–2244.

Parkinson's disease. Lancet, 365(9457), 410–412.

New England Journal of Medicine, 354(4), 424–425.

Journal of Medical Genetics, 42(11), 837–846.

Archives of Neurology, 61(12), 1898–1904.

Annals of Neurology, 56(3), 427–431.

regions of alpha-synuclein are associated with Parkinson's disease. Annals of

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's

Exome sequencing identifies the cause of a mendelian disorder. Nature Genetics,

(2005). Genetic screening for a single common LRRK2 mutation in familial

al. (2006). LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. The

Cloning of the gene containing mutations that cause PARK8-linked Parkinson's

(2009). Genomewide association study for susceptibility genes contributing to

(2005). Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.

al. (1996). Mapping of a gene for Parkinson's disease to chromosome 4q21-q23.

Mutation in the a-synuclein gene identified in families with Parkinson's disease.

Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.

Homozygous PINK1 C-terminus mutation causing early-onset parkinsonism.

wide association study identifies common variants at four loci as genetic risk

Complete genomic screen in Parkinson disease: Evidence for multiple genes.


**3** 

*Singapore* 

**Parkin and Parkinson's Disease** 

*1Department of Physiology, National University of Singapore, 2A\*STAR Duke-NUS Neuroscience Research Partnership,* 

Parkinson's disease (PD) is the most common neurodegenerative movement disorder affecting millions of predominantly elderly individuals worldwide. Originally described as "The Shaking Palsy" in 1817 by the British physician, James Parkinson, the disease is attended by a constellation of motoric deficits including bradykinesia (slowness in movements), postural instability, rigidity and tremor that ultimately result in near total immobility. Although pathological changes are distributed in the PD brain, the principal neuropathology that underlies the characteristic motor phenotype of PD patients is unequivocally the loss of midbrain dopaminergic (DA) neurons in the *substantia nigra pars compacta* (SNpc), which results in a severe depletion of striatal dopamine and thereby an impaired nigrostriatal system that otherwise allows an individual to execute proper, coordinated movements. This specific pattern of neurodegeneration in PD is often accompanied by the presence of eosinophilic intracytoplasmic inclusions known as Lewy bodies (LBs) in surviving neurons in the SN as well as in other affected brain regions such as the dorsal motor nucleus of the vagus, locus ceruleus (LC) and olfactory nuclei (Braak et al., 2003). In advanced stages of the disease, LB pathology can also be found in the limbic structures and neocortex (Braak et al., 2003). Nonmotor features arising from these extra-nigral neuronal lesions, including autonomic, sensory and cognitive dysfunctions, present additional sources of considerable consternation and disability for affected individuals (Olanow et al., 2008). Thus, although SN pathology is often regarded as the most important hallmark of PD, the disease is increasingly being recognized as a multi-system disorder affecting not only dopaminergic, but also noradrenergic, cholinergic

Despite intensive research, the etiology of PD remains poorly understood and no current treatments can unequivocally slow or stop the degenerative process. Current therapies for PD are palliative at best and the mainstay is pharmacologic intervention via DA replacement (e.g. through L-DOPA administration). Major drawbacks with current therapies include the inevitable loss of effectiveness and increasing drug-induced side effects as the disease progresses. Invariably, the debilitating nature and morbidity of the disease present significant healthcare, socio-economic and emotional problems. As the world population rapidly ages, these problems undoubtedly would also increase. Notably, a recent study by Dorsey et al projected that the number of PD cases in Europe's five most

**1. Introduction** 

and serotonergic systems (Alexander, 2004).

Shiam-Peng Tay1, Grace G.Y. Lim1,

*3National Neuroscience Institute* 

Calvin W.S. Yeo1 and Kah-Leong Lim1,2,3

