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

Hdl Handle:
http://hdl.handle.net/10147/128715
Title:
Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.
Authors:
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
Affiliation:
MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.
Citation:
Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. 2010, 167 (3):774-85 Neuroscience
Journal:
Neuroscience
Issue Date:
19-May-2010
URI:
http://hdl.handle.net/10147/128715
DOI:
10.1016/j.neuroscience.2010.02.035
PubMed ID:
20188146
Additional Links:
doi:10.1016/j.neuroscience.2010.02.035
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.
Item Type:
Article
Language:
en
MeSH:
Amino Acid Substitution; Amyotrophic Lateral Sclerosis; Animals; DNA-Binding Proteins; Disease Models, Animal; Genetic Predisposition to Disease; Inclusion Bodies; Membrane Proteins; Mice; Mice, Transgenic; Motor Neurons; Point Mutation; Protein Transport; Spinal Cord
ISSN:
1873-7544

Full metadata record

DC FieldValue Language
dc.contributor.authorTudor, E Len
dc.contributor.authorGaltrey, C Men
dc.contributor.authorPerkinton, M Sen
dc.contributor.authorLau, K-Fen
dc.contributor.authorDe Vos, K Jen
dc.contributor.authorMitchell, J Cen
dc.contributor.authorAckerley, Sen
dc.contributor.authorHortobágyi, Ten
dc.contributor.authorVámos, Een
dc.contributor.authorLeigh, P Nen
dc.contributor.authorKlasen, Cen
dc.contributor.authorMcLoughlin, D Men
dc.contributor.authorShaw, C Een
dc.contributor.authorMiller, C C Jen
dc.date.accessioned2011-04-27T09:10:09Z-
dc.date.available2011-04-27T09:10:09Z-
dc.date.issued2010-05-19-
dc.identifier.citationAmyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. 2010, 167 (3):774-85 Neuroscienceen
dc.identifier.issn1873-7544-
dc.identifier.pmid20188146-
dc.identifier.doi10.1016/j.neuroscience.2010.02.035-
dc.identifier.urihttp://hdl.handle.net/10147/128715-
dc.description.abstractCytoplasmic 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.-
dc.language.isoenen
dc.relation.urldoi:10.1016/j.neuroscience.2010.02.035en
dc.subject.meshAmino Acid Substitution-
dc.subject.meshAmyotrophic Lateral Sclerosis-
dc.subject.meshAnimals-
dc.subject.meshDNA-Binding Proteins-
dc.subject.meshDisease Models, Animal-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshInclusion Bodies-
dc.subject.meshMembrane Proteins-
dc.subject.meshMice-
dc.subject.meshMice, Transgenic-
dc.subject.meshMotor Neurons-
dc.subject.meshPoint Mutation-
dc.subject.meshProtein Transport-
dc.subject.meshSpinal Cord-
dc.titleAmyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology.en
dc.typeArticleen
dc.contributor.departmentMRC Centre for Neurodegeneration Research, Institute of Psychiatry, King's College London, London, UK.en
dc.identifier.journalNeuroscienceen
dc.description.provinceLeinster-

Related articles on PubMed

All Items in Lenus, The Irish Health Repository are protected by copyright, with all rights reserved, unless otherwise indicated.