Alpha-synuclein A30P point-mutation generates age-dependent nigrostriatal deficiency in mice.
Lewy bodies are mainly composed of alpha-synuclein (SNCA) and specific mutations in SNCA gene are related to familial forms of Parkinson's disease (PD). The purpose of our study was to generate a mouse line with A30P knock-in point mutation in SNCA gene and to test if a single point-mutation is able to turn otherwise normal SNCA into a toxic form. The behavioral profile of SNCA A30P mice was followed for 16 months. Generally, these mice are healthy and viable without any obvious abnormalities. Starting from the age of 13 months mice developed a significant deficit in motor performance tests related to nigrostriatal function (ink-test and beam walk). In other tests (motility boxes, rotarod) mice continuously performed normally. Moreover, SNCA A30P mice expressed the altered sensitivity to VMAT2 inhibitor reserpine, possibly reflecting a functional deficiency of dopamine. Indeed, mice at 15 months of age had significantly reduced levels of dopamine and its major metabolite DOPAC in the striatum, and reduced levels of dopamine in the mesolimbic system. The present study confirms that SNCA plays an important role in the development of PD and an insertion of a single point mutation is sufficient to generate age-related decline in specific motor performance. The generated mouse line has a potential to become a model for PD with comparable time course and phenotype.
Plaas
M
M
Department of Physiology, Center of Molecular and Clinical Medicine, University of Tartu, Tartu, Estonia.
Karis
A
A
Innos
J
J
Rebane
E
E
Baekelandt
V
V
Vaarmann
A
A
Luuk
H
H
Vasar
E
E
Koks
S
S
D000367:Age Factors; D000375:Aging / Q000235:genetics; D000818:Animals; D003342:Corpus Striatum / Q000502:physiology*; D004298:Dopamine / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019957:Motor Skills Disorders / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D013378:Substantia Nigra / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics*
D051844:alpha-Synuclein; D004298:Dopamine