Contributions
Abstract: 138
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Multiple Sclerosis (MS) is one of the most common causes for neurological disability in young adults, hallmarked by inflammatory lesions, de- and remyelination and axonal degeneration. Current treatment options are primarily directed at immunomodulaton or immunosuppression. In the progressive phase, when inflammation has abated and axonal injury and degeneration is the dominant pathology, treatment options are sparse. We could recently show that alterations in organelle transport are one of the earliest events in the cascade leading to axonal injury and degeneration. In the animal model experimental autoimmune encephalomyelitis (EAE) such transport deficits are pervasive and precede structural axon damage. While transport deficits recover in acute EAE models they persist in models of chronic neuroinflammation. Here we investigated the implications of the chronic transport deficits on mitochondrial distribution in axon collaterals and synapses in more detail. We induced EAE in genetically modified mouse lines that express mitochondrially targeted cyan fluorescent protein and traced DRG axon collaterals that pass through an inflammatory lesion by viral gene transfer. Our results show that in acute EAE, short lasting transport interruptions do not affect the distal mitochondrial content, while longer lasting transport deficits as observed in chronic neuroinflammation decrease the distal mitochondrial content and thereby diminish the energy supply of the distal axonal arbor. Moreover, healthy appearing axons not depleted of mitochondria showed a different mitochondrial distribution with depleted boutons and increased content in the extrasynaptic parts. While mitochondrial number and volume within the boutons was decreased, the number of boutons was unaltered. These results indicate that distal mitochondrial depletion might contribute to gray matter pathology concomitant with clinical deficits seen in EAE and MS.
Disclosure:
A.L. has received a travel grant by Genzyme.
C.S.: nothing to disclose. N.W.: nothing to disclose.
T.M.: nothing to disclose.
M.K.: nothing to disclose. Work in M.K."s laboratory is financed through grants from the Deutsche Forschungsgemeinschaft (DFG; Transregio 128), the German Federal Ministry of Research and Education (BMBF; Competence Network Multiple Sclerosis), the European Research Council under the European Union"s Seventh Framework Program (FP/2007-2013; ERC Grant Agreement n. 310932), the Hertie-Foundation and the ""Verein Therapieforschung für MS-Kranke e.V..""
T.M. is supported by the Center for Integrated Protein Science (Munich, EXC 114), the European Research Council under the European Union"s Seventh Framework Program (FP/2007-2013; ERC Grant Agreement n. 616791), and the German Center for Neurodegenerative Disease (DZNE Munich), DFG-funded collaborative research center 870. M.K., and T.M. are supported by the Munich Center for Systems Neurology (SyNergy; EXC 1010). M.K. and T.M. are supported by the DFG Priority Program 1710.
Abstract: 138
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Multiple Sclerosis (MS) is one of the most common causes for neurological disability in young adults, hallmarked by inflammatory lesions, de- and remyelination and axonal degeneration. Current treatment options are primarily directed at immunomodulaton or immunosuppression. In the progressive phase, when inflammation has abated and axonal injury and degeneration is the dominant pathology, treatment options are sparse. We could recently show that alterations in organelle transport are one of the earliest events in the cascade leading to axonal injury and degeneration. In the animal model experimental autoimmune encephalomyelitis (EAE) such transport deficits are pervasive and precede structural axon damage. While transport deficits recover in acute EAE models they persist in models of chronic neuroinflammation. Here we investigated the implications of the chronic transport deficits on mitochondrial distribution in axon collaterals and synapses in more detail. We induced EAE in genetically modified mouse lines that express mitochondrially targeted cyan fluorescent protein and traced DRG axon collaterals that pass through an inflammatory lesion by viral gene transfer. Our results show that in acute EAE, short lasting transport interruptions do not affect the distal mitochondrial content, while longer lasting transport deficits as observed in chronic neuroinflammation decrease the distal mitochondrial content and thereby diminish the energy supply of the distal axonal arbor. Moreover, healthy appearing axons not depleted of mitochondria showed a different mitochondrial distribution with depleted boutons and increased content in the extrasynaptic parts. While mitochondrial number and volume within the boutons was decreased, the number of boutons was unaltered. These results indicate that distal mitochondrial depletion might contribute to gray matter pathology concomitant with clinical deficits seen in EAE and MS.
Disclosure:
A.L. has received a travel grant by Genzyme.
C.S.: nothing to disclose. N.W.: nothing to disclose.
T.M.: nothing to disclose.
M.K.: nothing to disclose. Work in M.K."s laboratory is financed through grants from the Deutsche Forschungsgemeinschaft (DFG; Transregio 128), the German Federal Ministry of Research and Education (BMBF; Competence Network Multiple Sclerosis), the European Research Council under the European Union"s Seventh Framework Program (FP/2007-2013; ERC Grant Agreement n. 310932), the Hertie-Foundation and the ""Verein Therapieforschung für MS-Kranke e.V..""
T.M. is supported by the Center for Integrated Protein Science (Munich, EXC 114), the European Research Council under the European Union"s Seventh Framework Program (FP/2007-2013; ERC Grant Agreement n. 616791), and the German Center for Neurodegenerative Disease (DZNE Munich), DFG-funded collaborative research center 870. M.K., and T.M. are supported by the Munich Center for Systems Neurology (SyNergy; EXC 1010). M.K. and T.M. are supported by the DFG Priority Program 1710.