Parkin protects against the toxicity associated with mutant alpha-synuclein: Proteasome dysfunction selectively affects catecholaminergic neurons

Neurogenetics Laboratory, Mayo Clinic Jacksonville, Jacksonville, FL 32224, USA.
Neuron (Impact Factor: 15.05). 01/2003; 36(6):1007-19. DOI: 10.1016/S0896-6273(02)01125-X
Source: PubMed


One hypothesis for the etiology of Parkinson's disease (PD) is that subsets of neurons are vulnerable to a failure in proteasome-mediated protein turnover. Here we show that overexpression of mutant alpha-synuclein increases sensitivity to proteasome inhibitors by decreasing proteasome function. Overexpression of parkin decreases sensitivity to proteasome inhibitors in a manner dependent on parkin's ubiquitin-protein E3 ligase activity, and antisense knockdown of parkin increases sensitivity to proteasome inhibitors. Mutant alpha-synuclein also causes selective toxicity to catecholaminergic neurons in primary midbrain cultures, an effect that can be mimicked by the application of proteasome inhibitors. Parkin is capable of rescuing the toxic effects of mutant alpha-synuclein or proteasome inhibition in these cells. Therefore, parkin and alpha-synuclein are linked by common effects on a pathway associated with selective cell death in catecholaminergic neurons.

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    • "These interactions result in defects of substrate ubiquitination and transfer to UPS. Interestingly, parkin over-production prevents proteasome defects caused by α-synuclein (Petrucelli et al. 2002). Parkin also influences ubiquitination of the mitochondrial proteome, which significantly affects PD pathogenesis (Sarraf et al. 2013). "
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    ABSTRACT: Impairment of "protein quality control" in neurons is associated with etiopathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy. The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others. Although the primary events in etiopathogenesis of sporadic forms of these diseases are still unknown, it is clear that aging, in connection with decreased activity of ubiquitin proteasome system, is the most significant risk factor. In this review we discuss the pathogenic role and intracellular fate of the candidate molecules associated with onset and progression of AD and PD, the protein tau and α-synuclein in context with the function of ubiquitin proteasome system. We also discuss the possibility whether or not the strategies focused to re-establishment of neuroproteostasis via accelerated clearance of damaged proteins in proteasome could be a promising therapeutic approach for treatment of major neurodegenerative diseases.
    General Physiology and Biophysics 07/2015; DOI:10.4149/gpb_2015024 · 1.17 Impact Factor
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    • "Mutations in parkin result in DAergic neurodegeneration with increased oxidative stress, yet in the absence of Lewy bodies (Yang et al., 2006). It is known that overexpression of parkin is able to decrease α-synuclein protein aggregation (Petrucelli et al., 2002; Yang et al., 2003). DJ-1 encodes a protein of the peptidase C56 family. "
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    ABSTRACT: Manganese (Mn), is a trace metal required for normal physiological processes in humans. Mn levels are tightly regulated, as high levels of Mn result in accumulation in the brain and cause a neurological disease known as manganism. Manganism shares many similarities with Parkinson's disease (PD), both at the physiological level and the cellular level. Exposure to high Mn-containing environments increases the risk of developing manganism. Mn is absorbed primarily through the intestine and then released in the blood. Excessive Mn is secreted in the bile and excreted in feces. Mn enters and exits cells through a number of non-specific importers localized on the cell membrane. Mutations in one of the Mn exporters, SLC30A10 (solute carrier family 30, member 10), result in Mn induced toxicity with liver impairments and neurological dysfunction. Four PD genes have been identified in connection to regulation of Mn toxicity, shedding new light on potential links between manganism and PD.
    Frontiers in Genetics 08/2014; 5:265. DOI:10.3389/fgene.2014.00265
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    • "Despite the complexity of PD etiology, parkin appears to play a broadly protective role in maintaining neuronal function and viability. These protective effects extend to a variety of neurotoxins, mitochondrial poisons and misfolded proteins including: dopamine [5], rotenone and carbonyl cyanide 3-chlorophenylhydrazone [6], 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), excitotoxin (kainic acid) [7], unfolded protein stress response [8], β-amyloid precursor protein [6], Pael receptor [9], [10], proteasome inhibitors and α-synuclein [11], [12]. Enforced parkin expression also suppresses pathological consequences of PINK1 and DJ-1 gene deficiencies. "
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    ABSTRACT: Parkinson's disease (PD) is a neurodegenerative disorder of complex etiology characterized by the selective loss of dopaminergic neurons, particularly in the substantia nigra. Parkin, a tightly regulated E3 ubiquitin ligase, promotes the survival of dopaminergic neurons in both PD and Parkinsonian syndromes induced by acute exposures to neurotoxic agents. The present study assessed the potential of cell-permeable parkin (CP-Parkin) as a neuroprotective agent. Cellular uptake and tissue penetration of recombinant, enzymatically active parkin was markedly enhanced by the addition of a hydrophobic macromolecule transduction domain (MTD). The resulting CP-Parkin proteins (HPM13 and PM10) suppressed dopaminergic neuronal toxicity in cells and mice exposed to 6-hydroxydopamine (6-OHDH) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). These included enhanced survival and dopamine expression in cultured CATH.a and SH-SY5Y neuronal cells; and protection against MPTP-induced damage in mice, notably preservation of tyrosine hydroxylase-positive cells with enhanced dopamine expression in the striatum and midbrain, and preservation of gross motor function. These results demonstrate that CP-Parkin proteins can compensate for intrinsic limitations in the parkin response and provide a therapeutic strategy to augment parkin activity in vivo.
    PLoS ONE 07/2014; 9(7):e102517. DOI:10.1371/journal.pone.0102517 · 3.23 Impact Factor
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