Axonal transport of human α-synuclein slows with aging but is not affected by familial Parkinson's disease-linked mutations

Authors


Address correspondence and reprint requests to Michael K. Lee, Department of Pathology/Neuropathology, The Johns Hopkins University School of Medicine, 558 Ross Research Building/720 Rutland Avenue, Baltimore, Maryland 21205–2196, USA.
E-mail: mklee@jhmi.edu

Abstract

Biochemical and genetic abnormalities of α-synuclein (α-Syn) are implicated in the pathogenesis of Parkinson's disease (PD) and other α-synucleinopathies. The abnormal intraneuronal accumulations of α-Syn in Lewy bodies (LBs) and Lewy neurites (LNs) have implicated defects in axonal transport of α-Syn in the α-synucleinopathies. Using human (Hu) α-Syn transgenic (Tg) mice, we have examined whether familial PD (FPD)-linked mutations (A30P and A53T) alter axonal transport of Huα-Syn. Our studies using peripheral nerves show that Huα-Syn and Moα-Syn are almost exclusively transported in the slow component (SC) of axonal transport and that the FPD-linked α-Syn mutations do not have obvious effects on the axonal transport of α-Syn. Moreover, older pre-symptomatic A53T Huα-Syn Tg mice do not show gross alterations in the axonal transport of α-Syn and other proteins in the SC, indicating that the early stages of α-synucleinopathy in A53T α-Syn Tg mice are not associated with gross alterations in the slow axonal transport. However, the axonal transport of α-Syn slows significantly with aging. Because the rate of axonal transport affects the stability and accumulation of proteins in axons, age-dependent-slowing α-Syn is a likely contributor to axonal aggregation of α-Syn in α-synucleinopathy.

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