Inclusion body formation and neurodegeneration are parkin independent in a mouse model of alpha-synucleinopathy.
Mutations in the genes coding for alpha-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. Alpha-synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of alpha-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T alpha-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T alpha-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T alpha-synuclein-overexpressing mice are not altered in parkin null alpha-synuclein-overexpressing double-mutant mice. Our results demonstrate that mutant alpha-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by alpha-synuclein and parkin mutations may occur via independent mechanisms.
von Coelln
Rainer
R
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Thomas
Bobby
B
Andrabi
Shaida A
SA
Lim
Kah Leong
KL
Savitt
Joseph M
JM
Saffary
Roya
R
Stirling
Wanda
W
Bruno
Kristy
K
Hess
Ellen J
EJ
Lee
Michael K
MK
Dawson
Valina L
VL
Dawson
Ted M
TM
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D016631:Lewy Bodies / Q000378:metabolism* / Q000648:ultrastructure*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*; D051844:alpha-Synuclein / Q000378:metabolism*
D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein