Over-expression of alpha-synuclein in the nervous system enhances axonal degeneration after peripheral nerve lesion...

Wallerian degeneration in peripheral nerves occurs after a traumatic insult when the distal nerve part degenerates while peripheral macrophages enter the nerve stump and remove the accruing debris by phagozytosis. We used an experimental model to investigate the effect of either the absence or over-expression of alpha-synuclein (alpha-syn) after transecting the sciatic nerves of mice. alpha-Synuclein is a major component of Lewy bodies and its aggregation results in a premature destruction of nerve cells. It has also been found present in different peripheral nerves but its role in the axon remains still unclear. Following sciatic nerve transection in different mouse strains, we investigated the numbers of invading macrophages, the amounts of remaining myelin and axons 6 days after injury. All mice showed clear signs of Wallerian degeneration, but transgenic mice expressing human wild-type alpha-syn showed lower numbers of invading macrophages, less preserved myelin and significantly lower numbers of preserved axons in comparison with either knockout mice or a mouse strain with a spontaneous deletion of alpha-syn. The use of protein aggregation filtration blots and paraffin-embedded tissue blots displayed depositions of alpha-syn aggregates within sciatic nerve axons of transgenic mice. Thicker myelin sheaths and higher numbers of mitochondria were detected in old alpha-syn transgenic mice. In a human sural nerve, alpha-syn could also be identified within axons. Thus, alpha-syn and its aggregates are not only a component of Lewy bodies and synapses but also of axons and these aggregates might interfere with axonal transport. alpha-Synuclein transgenic mice represent an appropriate model for investigations on axonal transport in neurodegenerative diseases.