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Neuronal Death and Neurodegeneration

開催日 2014/9/11
時間 18:00 - 19:00
会場 Room I(311+312)
Chairperson(s) 岡澤 均 / Hitoshi Okazawa (東京医科歯科大学 / Tokyo Medical and Dental University, Japan)
渡部 和彦 / Kazuhiko Watabe (東京都医学総合研究所 神経変性病理 / ALS/Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Japan)

Endosomal SNAREs (vti1a/vti1b) double knockout mice show significant neuronal degeneration in central as well as peripheral nervous system

  • O1-I-6-1
  • Ajaya J Kunwar:1,2 M. Rickmann:2 G. FV Mollard:2 K. Krieglstein:3 
  • 1:Dept. of Anatomy, Nepalese Army Institute of Health Sciences - COM, Sanobharyang, Kathmandu, Nepal 2:Dept. of Anatomy/Neuroanatomy, Uni. Goettingen, Goettingen, Germany 3:Dept. of Anatomy/Mol. Embryology, Uni. Freiburg, Freiburg, Germany 

In eukaryotic cells, molecules need to be transported to their correct intracellular destination without compromising the structural integrity of cellular compartments to maintain homoeostasis and to allow appropriate signaling cascades in certain space and time. To achieve this, transport vesicles bud from an intracellular donor organelle and then target, dock and fuse with an acceptor organelle. SNARE proteins have been implicated as central in membrane trafficking events. SNAREs vti1a and vti1b share 30% similarity in their amino acid sequences and have a distinct but overlapping subcellular localization. Vti1a functions with trans-Golgi network/early endosomal fusion processes whereas vti1b is with late endosomal fusion/lysosomal degradation events. Mice deficient of both endosomal SNARE proteins, vti1a and vti1b, die at birth, whereas single knockouts and triallelic mice survive and reach normal age without difficulty. These KO mice have various changes in central (CNS) as well as peripheral nervous system (PNS). In CNS, substantia nigra neurons looks normal in E12.5 but at E14.5 they start to degenerate and their number are reduced to almost 50% at E18.5. Likewise, they show wide ventricles and lack several fibre tracts including anterior commisure. Corpus callosum thickness is greatly reduced and thalamocortical axons cannot cross pallio-subpallial border. Only a few corticothalamic fibres can reach thalamus as labeled by neurotracing dye DiI. On the other hand in PNS, KO mice show various degrees of neurodegeneration in different types of ganglia. Trigeminal and dorsal root ganglia show severe neurodegeneration (c.98%) whereas vestibular and cochlear ganglia show only 15-25% degeneration. This neurodegeneration was due to the lack of delivering efficient plasma membrane required during axonal growth cone formation. Overall phenotype suggests that neurons in CNS and PNS do require adequate endosomal traffic events to produce their normal axonal growth.

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