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Neuroprotective upregulation of endogenous alpha-synuclein precedes ubiquitination in cultured dopaminergic neurons


Musgrove, RE and King, AE and Dickson, TC, Neuroprotective upregulation of endogenous alpha-synuclein precedes ubiquitination in cultured dopaminergic neurons , Neurotoxicity Research , 19, (4) pp. 592-602. ISSN 1029-8428 (2011) [Refereed Article]

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DOI: doi:10.1007/s12640-010-9207-x


Alpha-synuclein is the major protein component of Lewy bodies—the pathological hallmark of Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Its accumulation into intracellular aggregates is implicated in the process of Lewy body formation. However, its roles in both normal function, and disease, remain controversial. Using a novel model of chronic oxidative stress in cultured dopaminergic and cortical neurons, we report that endogenous alpha-synuclein is upregulated in response to low dose toxicity. This response is conserved between subpopulations of cortical and dopaminergic neurons, and confers relative resistance to apoptosis following secondary insult. Additional acute oxidative stress leads to intracellular accumulation of alpha-synuclein. These punctate deposits colocalize with ubiquitin, which is central to proteosome-mediated protein degeneration, and is the second major component of Lewy bodies. The current results imply that differential levels of alpha-synuclein expression may influence neuronal vulnerability in chronic neurodegenerative diseases. They further support a ‘two hit’ hypothesis for Lewy body formation, whereby mild stress causes a protective upregulation of alpha-synuclein. However, such increased levels of alpha-synuclein may drive its accumulation, following additional toxic insult. Finally, these results support a common mechanism for degeneration of dopaminergic and cortical neurons, affected in PD, and DLB, respectively.

Item Details

Item Type:Refereed Article
Keywords:Alpha-synuclein; Oxidative stress; Neuroprotection; Dopaminergic; Cortical; Synucleinopathies
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Neurology and neuromuscular diseases
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Musgrove, RE (Dr Ruth Musgrove)
UTAS Author:King, AE (Professor Anna King)
UTAS Author:Dickson, TC (Professor Tracey Dickson)
ID Code:66708
Year Published:2011
Web of Science® Times Cited:12
Deposited By:Menzies Institute for Medical Research
Deposited On:2011-02-09
Last Modified:2011-05-03

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