ABSTRACT
Alpha-Synuclein is thought to play an important role in the pathology of Parkinson's disease (PD). Truncated forms of this protein can be found in PD brain extracts, and these species aggregate faster and are more susceptible to oxidative stress than the full-length protein. We investigated the effect of truncated alpha-synuclein on dopaminergic cells using a transgenic mouse expressing alpha-synuclein (1-120) driven by the rat tyrosine hydroxylase promoter on a mouse alpha-synuclein null background. We found a selective reduction in the yield of dopaminergic cells from transgenic embryonic ventral mesencephalic cell cultures. However, in vivo the substantia nigra/ventral tegmentum dopaminergic cell counts were not reduced in transgenics, although these mice are known to have reduced striatal dopamine. When transplanted to the striatum in the unilateral 6-hydroxydopamine-lesioned mouse model of PD, dopaminergic cells derived from transgenic embryonic ventral mesencephala were significantly smaller at 6 weeks, and showed a trend towards being less effective at ameliorating rotational asymmetry than those from control alpha-synuclein null mice. These results suggest that alpha-synuclein (1-120) renders dopaminergic cells more susceptible to stress, which may have important implications as to how this truncated protein might contribute to dopaminergic cell death in sporadic PD.
Subject(s)
Dopamine/metabolism , Mutant Proteins/metabolism , Neurons/metabolism , Parkinson Disease/metabolism , Parkinson Disease/pathology , alpha-Synuclein/chemistry , alpha-Synuclein/metabolism , Animals , Cell Count , Cell Size , Cells, Cultured , Disease Models, Animal , Embryo, Mammalian/metabolism , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/pathology , Neurons/transplantation , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Rats , Rotation , Substantia Nigra/embryology , Substantia Nigra/metabolism , Transgenes , Ventral Tegmental Area/transplantationABSTRACT
alpha-Synuclein belongs to a small group of natively unfolded proteins that can transiently bind to lipid membranes and acquire a partial alpha-helical conformation. Under certain pathogenic conditions, alpha-synuclein aggregates to form oligomers and insoluble fibrils with increased ss-sheet configuration. Although genetic mutations and multiplications of the gene have been found in familial cases, the mechanism by which this protein aggregates in sporadic cases of Parkinson's disease, dementia with Lewy bodies and multisystem atrophy is not fully understood. Here we review the function of alpha-synuclein and recent insight into the mechanisms by which it aggregates.
Subject(s)
Parkinson Disease/metabolism , alpha-Synuclein/physiology , Humans , Lewy Bodies/metabolism , Parkinson Disease/genetics , Parkinson Disease/pathology , Protein Processing, Post-Translational , Protein Structure, Tertiary , alpha-Synuclein/chemistry , alpha-Synuclein/geneticsABSTRACT
alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease based on mutations in familial cases of the disease and its presence in Lewy bodies. Here we show that over-expression of wild-type human alpha-synuclein is sufficient to induce inclusion formation in SH-SY5Y cells. In this cellular model, proteasome inhibition leads to an increase of alpha-synuclein accumulation in vivo without ubiquitylation. In accordance, we find that in vitro, unmodified alpha-synuclein can be directly degraded by the 20S proteasome. These findings suggest an ubiquitin-independent mechanism of proteasomal degradation for alpha-synuclein and other natively unfolded proteins.
