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Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology

journal contribution
posted on 2023-06-08, 13:34 authored by E L Tudor, C M Galtrey, M S Perkinton, K-F Lau, K J De Vos, J C Mitchell, S Ackerley, T Hortobágyi, E Vámos, Nigel LeighNigel Leigh, C Klasen, D M McLoughlin, C E Shaw, C C J Miller
Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.

History

Publication status

  • Published

Journal

Neuroscience

ISSN

1873-7544

Publisher

Elsevier

Issue

3

Volume

167

Page range

774-785

Department affiliated with

  • Clinical and Experimental Medicine Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-11-09

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