| RRC ID |
85353
|
| Author |
Dinh TTH, Imura C, Shiokawa M, Ayabe S, Yoshiki A, Inoue H, Amano T.
|
| Title |
A partial deletion of the Tardbp 3´UTR affects TDP-43 regulation and leads to motor dysfunction in mice.
|
| Journal |
Exp Anim
|
| Abstract |
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes the selective loss of motor neurons. A histopathological hallmark of ALS is the cytoplasmic aggregation of TDP-43, a ubiquitously expressed RNA-binding protein involved in transcription and splicing regulation. To prevent abnormal accumulation, TDP-43 controls its expression levels through an autoregulatory feedback loop. While most ALS studies have focused on pathogenic variants that impair the protein function of TDP-43, the mechanisms underlying endogenous TDP-43 dysregulation mediated by non-coding elements, including the 3´ untranslated region (3´UTR), remain incompletely understood. In this study, we generated a mouse model carrying a targeted deletion of the Tardbp 3´UTR that encompasses the TDP-binding region, polyadenylation signals, and alternative intronic sequences. Our findings demonstrate that the Tardbp 3´UTR is essential for normal mouse development. Loss of this region led to decreased Tardbp mRNA expression and embryonic lethality after gastrulation. Young heterozygous mice were phenotypically normal with no overt disruption in TDP-43 autoregulation. However, aged heterozygous mice displayed mild locomotor dysfunction accompanied by a modest increase in spinal cord TDP-43 protein levels and a reduction in motor neuron numbers. These findings indicate that regulatory elements within the Tardbp 3´UTR play a pivotal role in normal development and contribute to TDP-43 pathology relevant to ALS.
|
| Published |
2025-7-19
|
| DOI |
10.1538/expanim.25-0061
|
| PMID |
40691077
|
| PMC |
PMC12826566
|
| MeSH |
3' Untranslated Regions* / genetics
Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / physiopathology
Animals
DNA-Binding Proteins* / genetics
DNA-Binding Proteins* / metabolism
Disease Models, Animal
Gene Deletion*
Mice
Mice, Inbred C57BL
Motor Neurons / metabolism
Motor Neurons / pathology
Spinal Cord / metabolism
|
| IF |
1.574
|
| Resource |
| Human and Animal Cells |
293(RCB1637) |
| DNA material |
Achilles/pRSETB (RDB15982)
B6N Mouse BAC clone B6Ng01-222C01
pCAG-Achilles-Tardbp 3' UTR (RDB21123)
pCAG-Achilles-Tardbp deltaUTR (RDB21124)
pCMV-TARDBP-pA (RDB21125) |
