Immunohistochemical and subcellular localization of parkin protein: Absence of protein in autosomal recessive juvenile parkinsonism patients

Shimura, Hideki; Hattori, Nobutaka; Kubo, Shinichiro; Yoshikawa, Mutsuko; Kitada, Tohru; Matsumine, Hiroto; Asakawa, Shuichi; Minoshima, Shinsei; Yamamura, Yuichi; Shimizu, Nobuyoshi; Mizuno, Yoshikuni

doi:10.1002/1531-8249(199905)45:5<668::aid-ana19>3.0.co;2-z

Cited by 262 publications

(203 citation statements)

References 12 publications

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“…As is the case in conventional idiopathic PD, the neuropathologic changes of parkin-linked AR-JP are largely confined to the brain stem and include the loss of selected neurons and local gliosis. However, ␣-synuclein-and ubiquitin-positive neuronal inclusions, LBs, are generally absent in parkin-linked AR-JP (11)(12)(13).…”

supporting

confidence: 58%

Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Kim

Sung

et al. 2003

Journal of Biological Chemistry

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Mutations in the ␣-synuclein and parkin genes cause heritable forms of Parkinson's disease. In the present study, we examined the possible functional relationship between the parkin and ␣-synuclein genes in a conditionally immortalized embryonic hippocampal cell (H19-7) line. Whereas transient transfection of ␣-synuclein into neuronal H19-7 cells caused the formation of its intracytoplasmic inclusions and a significant cell death, the combined overexpression of parkin restored the ␣-synucleininduced decrease in cell viability to control levels. In addition, the overexpression of parkin was found to generate selective cleavage of ␣-synuclein. Furthermore, the cytoprotective effect of parkin on ␣-synuclein-induced cell death was not inhibited in the presence of a proteasome inhibitor. Interestingly, the overexpression of parkin induced the activation of an intracellular cysteine protease, calpain, but not caspase, and the cytoprotective effect of parkin on ␣-synuclein cytotoxicity was significantly inhibited by the presence of calpain-specific inhibitors. In conclusion, our results suggest that parkin accelerates the degradation of ␣-synuclein via the activation of the nonproteasomal protease, calpain, leading to the prevention of ␣-synuclein-induced cell death in embryonic hippocampal progenitor cells.

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confidence: 58%

Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Kim

Sung

et al. 2003

Journal of Biological Chemistry

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“…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). It has been hypothesized that accumulation of (as yet unidentified) proteins causes selective neuronal cell death in AR-JP without formation of Lewy bodies.…”

Section: Parkin (Gene Locus Park2 Omim 602544)mentioning

confidence: 71%

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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“…DISCUSSION The recessive heritability of Parkinson's disease caused by parkin gene lesions underscores the importance of parkin function for the survival of the dopaminergic neurons of substantia nigra pars compacta and suggests that its dysfunction can contribute to the disease progression in sporadic Parkinson's disease. This is corroborated by the detection of cleaved parkin fragments in substantia nigral tissue affected by Parkinson's disease and in Lewy bodies isolated from diseased tissue (30,31). Moreover, proteolytic inactivation of parkin may play a broader role in neurodegenerative settings as recently demonstrated by parkin's rapid catabolism upon hypoxia (32).…”

Section: Endogenous Caspase-8 But Not Endogenous Caspase-3 Cleaves mentioning

confidence: 99%

Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

Kahns

Kalai

Jakobsen

et al. 2003

Journal of Biological Chemistry

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Immunohistochemical and subcellular localization of parkin protein: Absence of protein in autosomal recessive juvenile parkinsonism patients

Cited by 262 publications

References 12 publications

Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Parkin Cleaves Intracellular α-Synuclein Inclusions via the Activation of Calpain

Genetics of Parkinsonism: a review

Caspase-1 and Caspase-8 Cleave and Inactivate Cellular Parkin

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