Journal
MOLECULAR BRAIN
Volume 13, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13041-020-0550-4
Keywords
Amyotrophic lateral sclerosis (ALS); TDP-43; TDP-43 knock-in mice
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Funding
- JSPS KAKENHI [18H02740, 18H04860, 19KK0214, 17H04986]
- Uehara Memorial Foundation
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [18H02740, 17H04986, 18H04860, 19KK0214] Funding Source: KAKEN
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Abnormal accumulation of TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein, is a pathological signature of amyotrophic lateral sclerosis (ALS). Missense mutations in the TARDBP gene are also found in inherited and sporadic ALS, indicating that dysfunction in TDP-43 is causative for ALS. To model TDP-43-linked ALS in rodents, we generated TDP-43 knock-in mice with inherited ALS patient-derived TDP-43(M337V) mutation. Homozygous TDP-43(M337V) mice developed normally without exhibiting detectable motor dysfunction and neurodegeneration. However, splicing of mRNAs regulated by TDP-43 was deregulated in the spinal cords of TDP-43(M337V) mice. Together with the recently reported TDP-43 knock-in mice with ALS-linked mutations, our finding indicates that ALS patient-derived mutations in the TARDBP gene at a carboxyl-terminal domain of TDP-43 may cause a gain of splicing function by TDP-43, however, were insufficient to induce robust neurodegeneration in mice.
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