Expression of A53T Mutant But Not Wild-Type α-Synuclein in PC12 Cells Induces Alterations of the Ubiquitin-Dependent Degradation System, Loss of Dopamine Release, and Autophagic Cell Death

By Leonidas Stefanis, K. E. Larsen, H. Rideout, D. Sulzer, L. Greene. Journal of Neuroscience, 2001

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α-Synuclein mutations have been identified in certain families with Parkinson's disease (PD), and α-synuclein is a major component of Lewy bodies. Other genetic data indicate that the ubiquitin-dependent proteolytic system is involved in PD pathogenesis. We have generated stable PC12 cell lines expressing wild-type or A53T mutant human α-synuclein. Lines expressing mutant but not wild-type α-synuclein show: (1) disruption of the ubiquitin-dependent proteolytic system, manifested by small cytoplasmic ubiquitinated aggregates and by an increase in polyubiquitinated proteins; (2) enhanced baseline nonapoptotic death; (3) marked accumulation of autophagic–vesicular structures; (4) impairment of lysosomal hydrolysis and proteasomal function; and (5) loss of catecholamine-secreting dense core granules and an absence of depolarization-induced dopamine release. Such findings raise the possibility that the primary abnormality in these cells may involve one or more deficits in the lysosomal and/or proteasomal degradation pathways, which in turn lead to loss of dopaminergic capacity and, ultimately, to death. These cells may serve as a model to study the effects of aberrant α-synuclein on dopaminergic cell function and survival.

Subfields: Cell Biology, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/6aee772795799a7d97c4140c715a92ede4f972eb

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Citations in the corpus

Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease (2002, background): “Overexpression of mutant forms of -synuclein in cultured neuronal cells leads to formation of cytoplasmic aggregates, disruption of the ubiquitin-dependent proteasomal degradation system, and cell degeneration (Stefanis et al., 2001; Tanaka et al., 2001).”
What is the role of protein aggregation in neurodegeneration? (2005, background): “org/uniprot/P37840">α-synuclein protein in cells grown in culture causes toxicit”
Parkinson's Disease Mechanisms and Models (2003, background): “…or flies (Masliah et et al., 2003), overexpression of synuclein inhibits the al., 2000; van der Putten et al., 2000; Feany and Bender, proteasome (Stefanis et al., 2001), and mutant synuclein 2000; Matsuoka et al., 2001; Giasson et al., 2002; Lee increases the sensitivity of cells to proteasome…”
α-Synuclein in Parkinson's disease. (2012, background): “…mutant, or under certain circumstances, WT, can induce proteasomal dysfunction in a number of cell-free, cellular, and in vivo settings (Stefanis et al. 2001; Tanaka et al. 2001; Petrucelli et al. 2002; Snyder et al. 2003), although this is not universally observed (Martin-Clemente et…”