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

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, P. N. Leigh, C. Klasen, D. M. McLoughlin, C. E. Shaw, C. C.J. Miller

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)774-785
Number of pages12
JournalNeuroscience
Volume167
Issue number3
DOIs
Publication statusPublished - May 1 2010

Keywords

  • Motor neuron disease
  • TAR-DNA-binding protein-43
  • Ubiquitin
  • Vesicle-associated membrane protein-associated protein-B

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology'. Together they form a unique fingerprint.

  • Cite this

    Tudor, E. L., Galtrey, C. M., Perkinton, M. S., Lau, K. F., De Vos, K. J., Mitchell, J. C., Ackerley, S., Hortobágyi, T., Vámos, E., Leigh, P. N., Klasen, C., McLoughlin, D. M., Shaw, C. E., & Miller, C. C. J. (2010). Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. Neuroscience, 167(3), 774-785. https://doi.org/10.1016/j.neuroscience.2010.02.035