Familial juvenile parkinsonism

Takahashi, Hitoshi; Ohama, Eisaku; Suzuki, Satoshi; Horikawa, Yo; Ishikawa, Atsushi; Morita, Takehito; Tsuji, Sho; Ikuta, Fusahiro

doi:10.1212/wnl.44.3_part_1.437

Cited by 281 publications

(160 citation statements)

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“…PD is characterized pathologically by the presence of cytoplasmic proteinaceous inclusions (Lewy bodies), which stain abundantly with ubiquitin (42). Patients with mutations in Parkin do not have Lewy bodies (43)(44)(45). Our observations that Parkin functions in the ubiquitin proteasome degradation pathway coupled with the postmortem observations suggest that Parkin function might contribute to the formation of Lewy bodies and that Lewy body formation may not be required for the development of PD.…”

Section: Discussionmentioning

confidence: 64%

Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1

Zhang

Gao

Chung

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

913

744

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P arkinson's disease (PD) is the second most prevalent neurodegenerative disorder, but the etiology remains poorly understood (1, 2). Patients with PD suffer from rigidity, slowness of movement, tremor, and disturbances of balance (1, 2). PD is characterized by the progressive loss of dopamine-containing neurons in the substantia nigra pars compacta (3, 4) and the accumulation of Lewy bodies, proteinaceous intracytoplasmic accumulations of eosinophilic material that stain for ubiquitin (5). Novel insights into the molecular mechanisms of the pathogenesis of PD have come from the identification of genes associated with rare forms of familial PD (6). Mutations in ␣-synuclein (A53T and A30P) are linked to autosomal dominant PD (7,8). This led to the discovery that ␣-synuclein is a major component of Lewy bodies and suggests that derangements in ␣-synuclein could be a major cause or contributor to the pathogenesis of sporadic PD (9, 10). Consistent with this notion are observations that overexpression of ␣-synuclein in transgenic fruit flies and mice causes a Parkinsonian phenotype and replicates many of the pathological features of PD (11-13).Other autosomal dominant genes or loci linked to PD have been described and include a mutation (I93M) in ubiquitin carboxyl-terminal-hydrolase-L1 (14), a member of the ubiquitin C-terminal hydrolase family that hydrolyzes small C-terminal adducts of ubiquitin to generate ubiquitin monomers and is involved in facilitating the degradation and processing of proteins through the 26 S proteasome. Thus, derangements in ubiquitin processing may be linked to the pathogenesis of PD. Linkages to chromosome 2P and 4P have been described, as well as yet to be identified loci, but the genes await identification (15-17).Mutations in the Parkin gene are responsible for autosomal recessive PD (18). Several Parkin-associated pedigrees have been described with both deletions and point mutations, as well as compound heterozygosity causing autosomal recessive PD (19)(20)(21). Recent studies suggest that mutations in Parkin are the major cause of autosomal recessive familial PD (19); thus, understanding the function of Parkin and how mutations interfere with the function of Parkin may provide novel insights into the pathogenesis of PD. The function of the Parkin protein remains unknown. However, Parkin shows mild homology to ubiquitin at the N terminus and contains two ring-finger motifs and an in-between ring-finger (IBR) domain at the C terminus (22). Recently, a few proteins with ring-finger motifs similar to Parkin were shown to be involved in E2-dependent ubiquitination (23-26). Ubiquitination requires the ATP-dependent activation of ubiquitin by the ubiquitin-activating enzyme E1. Ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme, which works in conjunction with an E3 ubiquitin-protein ligase to ubiquitinate substrate proteins (23,24). The existence of two ring-finger motifs and the N-terminal homology to ubiquitin suggests that Parkin may be involved in the ubiquitination pathw...

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Section: Discussionmentioning

confidence: 64%

Parkin functions as an E2-dependent ubiquitin– protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1

Zhang

Gao

Chung

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

913

744

View full text Add to dashboard Cite

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“…In 1998, deletions in the Parkin gene were reported in a set of Japanese families with autosomal recessive early-onset parkinsonism [171] with atypical features such as frequent dystonia, slow progression and hyperreflexia [218]. Neuropathological examination showed selective degeneration of nigrostriatal neurons, but no Lewy bodies [219].…”

Section: Genes Associated With Autosomal Recessive Pdmentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…Pathological changes include significant loss of dopaminergic neurons in the SN and milder changes in the locus coeruleus. Initially LBs were thought to be absent in the brain [218], but LBͲpositive cases have been reported in a reduced number of patients with parkin mutations [219]. [220].…”

Section: Parkinmentioning

confidence: 99%