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Siebert H.,University Medical Center Goettingen | Kahle P.J.,University of Tubingen | Kahle P.J.,German Center for Neurodegenerative Diseases | Kramer M.L.,University Medical Center Goettingen | And 4 more authors.
Journal of Neurochemistry | Year: 2010

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 -synuclein (-syn) after transecting the sciatic nerves of mice. -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 -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 -syn. The use of protein aggregation filtration blots and paraffin-embedded tissue blots displayed depositions of -syn aggregates within sciatic nerve axons of transgenic mice. Thicker myelin sheaths and higher numbers of mitochondria were detected in old -syn transgenic mice. In a human sural nerve, -syn could also be identified within axons. Thus, -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. -Synuclein transgenic mice represent an appropriate model for investigations on axonal transport in neurodegenerative diseases. © 2010 The Authors. Journal Compilation © 2010 International Society for Neurochemistry. Source

Govindarajan N.,University Hospital Freiburg | Govindarajan N.,German Center for Neurodegenerative Diseases | Rao P.,University Hospital Freiburg | Burkhardt S.,University Hospital Freiburg | And 8 more authors.
EMBO Molecular Medicine | Year: 2013

Histone deacetylases (HDACs) are currently being discussed as promising therapeutic targets to treat neurodegenerative diseases. However, the role of specific HDACs in cognition and neurodegeneration remains poorly understood. Here, we investigate the function of HDAC6, a class II member of the HDAC superfamily, in the adult mouse brain. We report that mice lacking HDAC6 are cognitively normal but reducing endogenous HDAC6 levels restores learning and memory and α-tubulin acetylation in a mouse model for Alzheimer's disease (AD). Our data suggest that this therapeutic effect is, at least in part, linked to the observation that loss of HDAC6 renders neurons resistant to amyloid-β-mediated impairment of mitochondrial trafficking. Thus, our study suggests that targeting HDAC6 could be a suitable strategy to ameliorate cognitive decline observed in AD. © 2012 The Authors. Source

Kamp F.,German Center for Neurodegenerative Diseases | Kamp F.,Ludwig Maximilians University of Munich | Exner N.,German Center for Neurodegenerative Diseases | Exner N.,Ludwig Maximilians University of Munich | And 15 more authors.
EMBO Journal | Year: 2010

Aggregation of α-synuclein (αS) is involved in the pathogenesis of Parkinson's disease (PD) and a variety of related neurodegenerative disorders. The physiological function of αS is largely unknown. We demonstrate with in vitro vesicle fusion experiments that αS has an inhibitory function on membrane fusion. Upon increased expression in cultured cells and in Caenorhabditis elegans, αS binds to mitochondria and leads to mitochondrial fragmentation. In C. elegans age-dependent fragmentation of mitochondria is enhanced and shifted to an earlier time point upon expression of exogenous αS. In contrast, siRNA-mediated downregulation of αS results in elongated mitochondria in cell culture. αS can act independently of mitochondrial fusion and fission proteins in shifting the dynamic morphologic equilibrium of mitochondria towards reduced fusion. Upon cellular fusion, αS prevents fusion of differently labelled mitochondrial populations. Thus, αS inhibits fusion due to its unique membrane interaction. Finally, mitochondrial fragmentation induced by expression of αS is rescued by coexpression of PINK1, parkin or DJ-1 but not the PD-associated mutations PINK1 G309D and parkin Î "1-79 or by DJ-1 C106A. © 2010 European Molecular Biology Organization. All Rights Reserved. Source

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