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

ABSTRACT 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.

14 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "The expression of mutant alpha-synuclein induces the formation of filaments which interact directly with the 20S core of the proteasome and decrease its proteolytic activity (Lindersson et al., 2004). This deficit in proteasome function is ameliorated by the concomitant expression of the E3 ligase Parkin (Petrucelli et al., 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Control of proper protein synthesis, function, and turnover is essential for the health of all cells. In neurons these demands take on the additional importance of supporting and regulating the highly dynamic connections between neurons that are necessary for cognitive function, learning, and memory. Regulating multiple unique synaptic protein environments within a single neuron while maintaining cell health requires the highly regulated processes of ubiquitination and degradation of ubiquitinated proteins through the proteasome. In this review, we examine the effects of dysregulated ubiquitination and protein clearance on the handling of disease-associated proteins and neuronal health in the most common neurodegenerative diseases.
    Frontiers in Molecular Neuroscience 07/2014; 7:63. DOI:10.3389/fnmol.2014.00063 · 4.08 Impact Factor
Show more


14 Reads
Available from