Alpha-Synuclein affects neurite morphology, autophagy, vesicle transport and axonal degeneration in CNS neurons

J. C. Koch, F. Bitow, J. Haack, Z. Hedouville, J. N. Zhang, L. Tönges, U. Michel, L. M.A. Oliveira, T. M. Jovin, J. Liman, L. Tatenhorst, M. Bähr, P. Lingor

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100 Scopus citations

Abstract

Many neuropathological and experimental studies suggest that the degeneration of dopaminergic terminals and axons precedes the demise of dopaminergic neurons in the substantia nigra, which finally results in the clinical symptoms of Parkinson disease (PD). The mechanisms underlying this early axonal degeneration are, however, still poorly understood. Here, we examined the effects of overexpression of human wildtype alpha-synuclein (aSyn-WT), a protein associated with PD, and its mutant variants aSyn-A30P and -A53T on neurite morphology and functional parameters in rat primary midbrain neurons (PMN). Moreover, axonal degeneration after overexpression of aSyn-WT and -A30P was analyzed by live imaging in the rat optic nerve in vivo.We found that overexpression of aSyn-WT and of its mutants A30P and A53T impaired neurite outgrowth of PMN and affected neurite branching assessed by Sholl analysis in a variant-dependent manner. Surprisingly, the number of primary neurites per neuron was increased in neurons transfected with aSyn. Axonal vesicle transport was examined by live imaging of PMN co-transfected with EGFPlabeled synaptophysin. Overexpression of all aSyn variants significantly decreased the number of motile vesicles and decelerated vesicle transport compared with control. Macroautophagic flux in PMN was enhanced by aSyn-WT and -A53T but not by aSyn-A30P. Correspondingly, colocalization of aSyn and the autophagy marker LC3 was reduced for aSyn-A30P compared with the other aSyn variants. The number of mitochondria colocalizing with LC3 as a marker for mitophagy did not differ among the groups. In the rat optic nerve, both aSyn-WT and -A30P accelerated kinetics of acute axonal degeneration following crush lesion as analyzed by in vivo live imaging. We conclude that aSyn overexpression impairs neurite outgrowth and augments axonal degeneration, whereas axonal vesicle transport and autophagy are severely altered.

Original languageEnglish
Article numbere1811
JournalCell Death and Disease
Volume6
Issue number7
DOIs
StatePublished - 9 Jul 2015
Externally publishedYes

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