The effect of truncated human alpha-synuclein (1-120) on dopaminergic cells in a transgenic mouse model of Parkinson's disease.
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.
Michell
A W
AW
Department of Clinical Neuroscience, University of Cambridge and Cambridge Centre for Brain Repair, Cambridge, CB2 2PY, UK. awmichell@gmail.com
Tofaris
G K
GK
Gossage
H
H
Tyers
P
P
Spillantini
M G
MG
Barker
R A
RA
D000818:Animals; D002452:Cell Count; D048429:Cell Size; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012399:Rotation; D013378:Substantia Nigra / Q000196:embryology / Q000378:metabolism; D019076:Transgenes; D017557:Ventral Tegmental Area / Q000637:transplantation; D051844:alpha-Synuclein / Q000737:chemistry* / Q000378:metabolism*
D050505:Mutant Proteins; D010446:Peptide Fragments; D051844:alpha-Synuclein; D004298:Dopamine