Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q

Mori, Hiromu; Kondo, Tomoyoshi; Yokochi, Masayuki; Matsumine, Hiroto; Nakagawa‐Hattori, Yuko; Miyake, Takao; Suda, K; Mizuno, Y

doi:10.1212/wnl.51.3.890

Cited by 352 publications

(268 citation statements)

References 2 publications

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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: 63%

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: 63%

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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“…Mutations in the parkin gene are therefore considered to cause loss of ubiquitinprotein ligase activity (Shimura et al 2000). The main histopathological difference between patients with parkin mutations and those with sporadic PD are the absence of Lewy bodies (despite Chen et al 2000) and the restriction of neuronal loss to the substantia nigra and locus caeruleus in patients with parkin mutations (Mori et al 1998). Pathological studies of the brains of patients with AR-JP showed absence of parkin protein (Shimura et al 1999).…”

Section: Parkin (Gene Locus Park2 Omim 602544)mentioning

confidence: 99%

Genetics of Parkinsonism: a review

VAUGHAN¹,

DAVIS²,

WOOD³

2001

Annals of Human Genetics

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Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

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“…Furthermore, many of the monogenic mutations do not lead to development of LBs, a feature that also may be observed in sporadic PD, as well as after administration MPTP. These observations demonstrate that neurodegeneration can occur without the presence of LBs, both in familial and sporadic forms of PD (102,103).…”

Section: Pathological Hallmarksmentioning

confidence: 56%

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

et al. 2011

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Pathologic and biochemical studies of juvenile parkinsonism linked to chromosome 6q

Cited by 352 publications

References 2 publications

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

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

Genetics of Parkinsonism: a review

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

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