Neuroprotective upregulation of endogenous α-synuclein precedes ubiquitination in cultured dopaminergic neurons.
α-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 α-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 α-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 α-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 α-synuclein. However, such increased levels of α-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.
Musgrove
R E J
RE
Wicking Dementia Research and Education Centre, Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7000, Australia.
King
A E
AE
Dickson
T C
TC
D000818:Animals; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000166:cytology / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D051844:alpha-Synuclein / Q000096:biosynthesis*
D018696:Neuroprotective Agents; D051844:alpha-Synuclein