Axonal transport of human alpha-synuclein slows with aging but is not affected by familial Parkinson's disease-linked mutations.
Biochemical and genetic abnormalities of alpha-synuclein (alpha-Syn) are implicated in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. The abnormal intraneuronal accumulations of alpha-Syn in Lewy bodies (LBs) and Lewy neurites (LNs) have implicated defects in axonal transport of alpha-Syn in the alpha-synucleinopathies. Using human (Hu) alpha-Syn transgenic (Tg) mice, we have examined whether familial PD (FPD)-linked mutations (A30P and A53T) alter axonal transport of Hualpha-Syn. Our studies using peripheral nerves show that Hualpha-Syn and Moalpha-Syn are almost exclusively transported in the slow component (SC) of axonal transport and that the FPD-linked alpha-Syn mutations do not have obvious effects on the axonal transport of alpha-Syn. Moreover, older pre-symptomatic A53T Hualpha-Syn Tg mice do not show gross alterations in the axonal transport of alpha-Syn and other proteins in the SC, indicating that the early stages of alpha-synucleinopathy in A53T alpha-Syn Tg mice are not associated with gross alterations in the slow axonal transport. However, the axonal transport of alpha-Syn slows significantly with aging. Because the rate of axonal transport affects the stability and accumulation of proteins in axons, age-dependent-slowing alpha-Syn is a likely contributor to axonal aggregation of alpha-Syn in alpha-synucleinopathy.
Li
Wenxue
W
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA.
Hoffman
Paul N
PN
Stirling
Wanda
W
Price
Donald L
DL
Lee
Michael K
MK
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D010525:Peripheral Nerves / Q000378:metabolism; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein