Shimura, H. et al. Familial Parkinson disease gene product, Parkin, is a ubiquitin-protein ligase. Nat. Genet. 25, 302-305

Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
Nature Genetics (Impact Factor: 29.35). 08/2000; 25(3):302-5. DOI: 10.1038/77060
Source: PubMed


Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.

Download full-text


Available from: Shuichi Asakawa, Mar 26, 2015
  • Source
    • "Both hereditary and environmental factors are thought to be involved in the etiology of PD. Currently, causative genes in hereditary PD have been identified by genetic linkage analyses, including a-Synuclein (o.-Syn) (PARKI, PARK4), parkin (PARK2) and D|-1 (PARK7) (Polymeropoulos ef al.1997;Krtada et al. 1998; Shimura et a.2000; Bonifatr et a\.2003). "
    [Show description] [Hide description]
    DESCRIPTION: Parkinson's disease (PD) is a neurodegenerative movement disorder characterized by degeneration of dopaminergic neurons in the midbrain and formation of Lewy bodies. The molecular mechanism of the selectivity to dopamine-containing neurons is yet unclear. Previously we investigated the biochemical characteristics and degradation pathway of tyrosine hydroxylase, which is selectively expressed in catecholaminergnic neurons, and found that phosphorylated tyrosine hydroxylase at Ser40 (p40-TH) formed insoluble intracellular inclusions tightly co-localized with ubiquitin by inhibition of a proteasome system in NGF-differentiated PC12D cells (Kawahata et al., 2009). Here we examined the immunoreactivity against anti-TH and anti-p40-TH antibodies in postmortem brains from PD patients. We found that brainstem-type Lewy bodies were immunoreactive to anti-TH antibody and that the cytosol of some neurons was immunopositive to anti-p40-TH antibody. These data indicate p40-TH is one of the components of the Lewy bodies in postmortem brains from PD patients, suggesting the possibility that p40-TH is involved in the formation of inclusion bodies in human midbrain.
    Full-text · Research · Dec 2015
    • "conformation by the REP, which folds back from a region between IBR and RING2. It has been shown before that p.T240R does not interact with the E2 enzyme UbcH7 [Shimura et al., 2000]. In accordance with this, MDS indicated that it might prevent the release of the REP, a prerequisite for E2 binding [Caulfield et al., 2014], whereas the interaction surface for E2 binding stays largely intact. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the PARKIN/PARK2 gene that result in loss-of-function of the encoded, neuroprotective E3 ubiquitin ligase Parkin cause recessive, familial early-onset Parkinson disease. As an increasing number of rare Parkin sequence variants with unclear pathogenicity are identified, structure-function analyses will be critical to determine their disease relevance. Depending on the specific amino acids affected, several distinct pathomechanisms can result in loss of Parkin function. These include disruption of overall Parkin folding, decreased solubility, and protein aggregation. However pathogenic effects can also result from misregulation of Parkin autoinhibition and of its enzymatic functions. In addition, interference of binding to coenzymes, substrates, and adaptor proteins can affect its catalytic activity too. Herein, we have performed a comprehensive structural and functional analysis of 21 PARK2 missense mutations distributed across the individual protein domains. Using this combined approach, we were able to pinpoint some of the pathogenic mechanisms of individual sequence variants. Similar analyses will be critical in gaining a complete understanding of the complex regulations and enzymatic functions of Parkin. These studies will not only highlight the important residues, but will also help to develop novel therapeutics aimed at activating and preserving an active, neuroprotective form of Parkin.
    No preview · Article · Aug 2015 · Human Mutation
  • Source
    • "Elucidation of the pathogenetic mechanism of familial cases, besides being strategic in designing predictive and therapeutic measures for these cases, can provide clues in identifying susceptible sites and networks, whose acquired alterations might be involved/responsible for development and progress in the life-course of sporadic PD. More than 100 different pathogenetic mutations have so far been identified in the parkin (PARK2) gene, encoding parkin, which belongs to the ring between ring fingers (RBR) class of E3 ubiquitin ligases [4] [5]. It is believed that loss of the ubiquitin ligase activity in the parkin mutants impairs degradation by the ubiquitin–proteasome system of specific substrates with accumulation of non-ubiquitinated toxic products leading to neurodegeneration [6] [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is the most common neurodegenerative movement disorder caused primarily by selective degeneration of the dopaminergic neurons in substantia nigra. In this work the proteomes extracted from primary fibroblasts of two unrelated, hereditary cases of PD patients, with different parkin mutations, were compared with the proteomes extracted from commercial adult normal human dermal fibroblasts (NHDF) and primary fibroblasts from the healthy mother of one of the two patients. The results show that the fibroblasts from the two different cases of parkin-mutant patients display analogous alterations in the expression level of proteins involved in different cellular functions, like cytoskeleton structure-dynamics, calcium homeostasis, oxidative stress response, proteins and RNA processing. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Biochimica et Biophysica Acta
Show more