Park1

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PARK1 is an autosomal dominant familial PD caused by mutations of alpha-synuclein

(SNCA). Clinical features of PARK1 were first described by Golbe et al. (1990) on large autosomal dominant kindreds immigrated to USA from Contursi, a village in the hills of Salerno Province in southern Italy. Ancestors of this family are believed to have moved to Italy from Greece. Clinical features consist of L-dopa-responsive parkinsonism and variable degrees of cognitive impairment. The average age of onset of the original families reported by Golbe et al. (1990) was 46.5 ± 10.8 years (range, 28-68, N = 33).

Alpha-synuclein has been mapped to the long arm of chromosome 4 at 4q21-q23. To date, 3 missense mutations, i.e., A30P (Kriiger et al., 1998), E46K (Zarranz et al., 2004), and A53T (Polymeropoulos et al., 1997) and triplication (Singleton et al., 2003) and duplication (Chartier-Harlin et al., 2004; Ibenez et al., 2004) of the entire alpha-synuclein are known (Fig. 1). Alpha-synuclein is a neuron-specific protein localized mainly in the presynaptic terminal membranes and synaptic vesicles. Although the function of alpha-synuclein is not well known, aggregated alpha-synuclein is accumulated in the nigral neurons in PD indicating that alpha-synuclein plays an important role in the pathogenesis of PD. Recently reported families with triplication and duplication of alpha-synuclein suggest that overexpression of normal alpha-synuclein per se is neurotoxic to nigral neurons.

Name

Inheritance

Locus

Gene

PARK1

AD

4q21-23

a-synuclein

(SNCA)

PARK2

AR

6q25.2-27

parkin

PARK3

AD

2p13

unknown

PARK4

AD

4q21-23

a-synuclein

PARK5

AD

4p14

UCH-L1

PARK6

AR

1p35-36

PINK1

PARK7

AR

1p36

DJ-1

PARK8

AD

12p11.2-q13.1

LRRK2/

dardarin

PARK9

AR

1p36

unknown

PARK10

AD/AR/SP

1p32

unknown

PARK11

AD

2q36-37

unknown

AD autosomal dominant, AR autosomal recessive, SP sporadic

AD autosomal dominant, AR autosomal recessive, SP sporadic

Regarding the relationship between the types of mutation and clinical features, triplication and E46K mutations are associated with dementia in addition to parkinsonism and wide-spread neuropathologic changes with cortical Lewy bodies in addition to nigral neurodegeneration (Farrer et al., 1999; Zarranz et al., 2004). Actually neuropathological characteristics are consistent with those of diffuse Lewy body disease. On the other hand, duplication was associated with pure L-dopa-responsive parkinsonism without dementia.

Ala53Thr mutation is associated with variable degrees of cognitive impairment. Ala30Pro is less likely to show cognitive impairment.

Functions of alpha-synuclein are not well known. Alpha-synuclein is a natively unfolded brain specific protein consisting of 140 amino acids without significant amount of secondary structure (Weinreb et al., 1996). From its localization in presynaptic terminals, it has been speculated that it may be related to neurotransmitter regulation. Alpha-synuclein has a tendency for self-aggregation and oligomer formation. Soluble oligomers ultimately form insoluble aggregates, which are the major component of Lewy bodies (Spillantini et al., 1998). Particularly, oligomers of alpha-synuclein are toxic to neurons inducing release of dopamine into the cytoplasm from synaptic vesicles (Volles and Lansbury, 2002), impairment of 26S prote-asome (Snyder et al., 2003), and mitochondrial dysfunctions (Tanaka et al., 2001). Mitochondrial impairment results in reduced ATP synthesis. As 26S proteasome is an ATP-dependent protein degrading enzyme, mitochondrial impairment reduces its catalytic activity. Thus vicious cycles are formed within nigral neurons leading them to slowly progressing neuronal death. Mutated alpha-synuclein proteins show increased tendency for self-aggregation (El Agnuf et al., 1998).

Fig. 1. Schematic presentation of the exons of alpha-synuclein and its mutations. Three missense mutations, duplication (thin line) and triplication (thick line) are known. Closed diamonds indicate approximate positions of the KTKEGV repeats. NAC represents non-amyloid component of the senile plaque

This is likely to be a reason for earlier onset of ages in familial PD due to alpha-synuclein mutations compared with sporadic PD. Furthermore, aggregated insoluble alpha-synuclein proteins are likely to impair transport of vital substances within nigral neurons. The insoluble aggregate of alpha-synuclein is highly phosphorylated at Ser-129 (Fujiwara et al., 2002).

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