Co-association of parkin and α-synuclein

Choi, Peter S.; Golts, Natalie; Snyder, Heather M.; Chong, Matthew; Petrucelli, Leonard; Hardy, John; Sparkman, Dennis R.; Cochran, Elizabeth J.; Lee, Jack M.; Wolozin, Benjamin

doi:10.1097/00001756-200109170-00017

Cited by 70 publications

(48 citation statements)

References 17 publications

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“…Alternatively, differences in protein-protein interaction may have been the result of differences in specific cellular environments. Consistent with this view, parkin was reported to bind to ␣-synuclein, which seemed to be nonglycosylated, considering its molecular size in human neuroblastoma BE-M17 cells under basal as well as under oxidative conditions (18). Double staining of PD brains shows that both parkin and ␣-synuclein are co-localized in the same pathological structures, such as in LB and axonal spheroid, indicating that the interaction between ␣-synuclein and parkin somehow contributes to the pathophysiology of PD.…”

Section: Discussionmentioning

confidence: 66%

“…The substrate proteins for parkin remain largely unknown, with the exception of CDCrel-1 (15) and the Pael receptor (16). In PD, parkin is co-localized in some LBs (17) and all axonal spheroids (18), which contain aggregated ␣-synuclein. The association be-tween parkin and ␣-synuclein in LB suggests that parkin interacts with ␣-synuclein, and this interaction may play a role in the pathogenesis of PD.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

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

Kim

Sung

et al. 2003

Journal of Biological Chemistry

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“…It is noteworthy, however, that both α-synuclein and parkin, which are components of Lewy bodies (abnormal aggregates found in PD neurons), can bind to each other in vitro (40), that α-synuclein can bind to CCO (41), and that mitochondrial respiratory chain inhibitors can stimulate aggregation of α-synuclein into Lewy bodies in vitro (42,43).…”

Section: Parkinson Diseasementioning

confidence: 99%

Neuronal degeneration and mitochondrial dysfunction

Schon¹,

Manfredi²

2003

J. Clin. Invest.

216

184

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Over the last decade, the underlying genetic bases of several neurodegenerative disorders, including Huntington disease (HD), Friedreich ataxia, hereditary spastic paraplegia, and rare familial forms of Parkinson disease (PD), Alzheimer disease (AD), and amyotrophic lateral sclerosis (ALS), have been identified. However, the etiologies of sporadic AD, PD, and ALS, which are among the most common neurodegenerative diseases, are still unclear, as are the pathogenic mechanisms giving rise to the various, and often highly stereotypical, clinical features of these diseases. Despite the differential clinical features of the various neurodegenerative disorders, the fact that neurons are highly dependent on oxidative energy metabolism has suggested a unified pathogenetic mechanism of neurodegeneration, based on an underlying dysfunction in mitochondrial energy metabolism.Mitochondria are the seat of a number of important cellular functions, including essential pathways of intermediate metabolism, amino acid biosynthesis, fatty acid oxidation, steroid metabolism, and apoptosis. Of key importance to our discussion here is the role of mitochondria in oxidative energy metabolism. Oxidative phosphorylation (OXPHOS) generates most of the cell's ATP, and any impairment of the organelle's ability to produce energy can have catastrophic consequences, not only due to the primary loss of ATP, but also due to indirect impairment of "downstream" functions, such as the maintenance of organellar and cellular calcium homeostasis. Moreover, deficient mitochondrial metabolism may generate reactive oxygen species (ROS) that can wreak havoc in the cell. It is for these reasons that mitochondrial dysfunction is such an attractive candidate for an "executioner's" role in neuronal degeneration.The mitochondrion is the only organelle in the cell, aside from the nucleus, that contains its own genome and genetic machinery. The human mitochondrial genome (1) is a tiny 16.6-kb circle of double-stranded mitochondrial DNA (mtDNA) (Figure 1). It encodes 13 polypeptides, all of which are components of the respiratory chain/OXPHOS system, plus 24 genes, specifying two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs), that are required to synthesize the 13 polypeptides. Obviously, an organelle as complex as a mitochondrion requires more than 37 gene products; in fact, about 850 polypeptides, all encoded by nuclear DNA (nDNA), are required to build and maintain a functioning organelle. These proteins are synthesized in the cytoplasm and are imported into the organelle, where they are partitioned into the mitochondrion's four main compartments -the outer mitochondrial membrane (OMM), the inner mitochondrial membrane (IMM), the intermembrane space (IMS), and the matrix, located in the interior (the organelle's "cytoplasm"). Of the 850 proteins, approximately 75 are structural components of the respiratory complexes ( Figure 2) and at least another 20 are required to assemble and maintain them in working order. The five complexes of the respiratory chain...

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“…Concerning the interaction between LRRK2 and α-synuclein in late onset PD, biochemical studies have demonstrated a functional link [240]. Evidence of α-synuclein and parkin interaction was noted in relationship with toxic effect of α-synuclein accumulation on parkin solubility which aggregation in intraneuronal inclusions induces cell dysfunction [241].…”

Section: Genes' Products Relations and Mechanisms Implicated In Mendementioning

confidence: 99%

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

Popescu¹

2016

Med Clin Rev

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Parkinson's disease (PD) etiology is based upon interactions between genetic susceptibility and the environmental exposure. Multiple environmental factors inducing oxidative stress, mitochondrial damage, impairment of the neuroprotective and autophagic mechanisms are responsible for dopaminergic neurons death. Defining the contributions of genetic and environmental factors, may have important implications for understanding the pathogenesis of PD. The linkage analysis in Mendelian forms of PD especially in multiplex highly penetrant families is essential to elucidate biological mechanisms for PD susceptibility. Concerning the monogenic forms of PD were found mutations in 7 genes of AD transmission (SNCA, LRRK2, GIGYF2, VPS35, EIF4G1, HTRA2, TMEM230) and even more in those of AR transmission. This review aims to give an overview of the existing evidence of multiples molecular pathways involving cytoplasmic organelles' function, neurodevelopmental mechanisms, synaptic vesicles endocytosis and trafficking, maintaining the integrity of the cytoskeleton and axonal transport in neurons. Understanding the molecular mechanisms following the identification of genes mutations and low-penetrance susceptibility alleles in familial and sporadic PD patients by genotyping technology and functional studies represent an essential step for the development of adequate biomarkers and potent therapies.

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Co-association of parkin and α-synuclein

Cited by 70 publications

References 17 publications

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

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

Neuronal degeneration and mitochondrial dysfunction

Mechanisms Implicated in Parkinson Disease from Genetic Perspective

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