Abstract
Familial ALS patients with TDP-43 gene mutations and sporadic ALS patients share common TDP-43 neuronal pathology. To delineate mechanisms underlying TDP-43 proteinopathies, transgenic mice expressing A315T, M337V or wild type human TDP-43 were generated. Multiple TDP-43 founders developed a severe early motor phenotype that correlated with TDP-43 levels in spinal cord. Three A315T TDP-43 lines developed later onset paralysis with cytoplasmic ubiquitin inclusions, gliosis and TDP-43 redistribution and fragmentation. The WT TDP-43 mouse line with highest spinal cord expression levels remains asymptomatic, although these mice show spinal cord pathology. One WT TDP-43 line with high skeletal muscle levels of TDP-43 developed a severe progressive myopathy. Over-expression of TDP-43 in vivo is sufficient to produce progressive motor phenotypes by a toxic gain of function paradigm. Transgenic mouse lines expressing untagged mutant and wild type TDP-43 under the same promoter represent a powerful new model system for studying TDP-43 proteinopathies in vivo.
Original language | English (US) |
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Pages (from-to) | 404-414 |
Number of pages | 11 |
Journal | Neurobiology of Disease |
Volume | 40 |
Issue number | 2 |
DOIs | |
State | Published - Nov 2010 |
Keywords
- ALS
- Inclusions
- Motor neuron
- Myopathy
- Neurodegeneration
- TDP-43
ASJC Scopus subject areas
- Neurology