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| Status |
Public on Jan 09, 2023 |
| Title |
A TDP-43 acetylation-mimic mutation that disrupts RNA-binding drives FTLD-like neurodegeneration in a mouse model of sporadic TDP-43 proteinopathy |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
TDP-43 proteinopathies including frontotemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS) are devastating neurodegenerative disorders characterized by aggregation and mislocalization of the nucleic-acid binding protein TDP-43 and subsequent neuronal dysfunction. Here, we developed an endogenous model of sporadic TDP-43 proteinopathy based on the principle that disease-associated TDP-43 acetylation at lysine 145 (K145) alters TDP-43 conformation, impairs its RNA-binding capacity, and induces downstream mis-regulation of target genes. Expression of aberrant acetylation-mimic TDP-43K145Q resulted in stress-induced phase-separated nuclear TDP-43 foci formation and loss-of-TDP-43-function in mouse primary neurons and human induced pluripotent stem cell (iPSC)-derived neurons. Aged mice harboring the single TDP-43K145Q mutation recapitulate several key hallmarks of neurodegenerative proteinopathies, including progressive TDP-43 phosphorylation and insolubility, cytoplasmic mis-localization, widespread transcriptomic and splicing alterations, and cognitive dysfunction. Our study supports a model in which aberrant TDP-43 acetylation drives neuronal dysfunction and cognitive decline through alternative splicing and transcription of genes important in synaptic plasticity and apoptosis, providing a new paradigm to interrogate FTLD disease mechanisms and uncover disease-modifying therapeutics.
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| Overall design |
Total RNAseq of mouse hippocampus and cortex, comparing TDP43-KQ vs TDP43-WT in 18-month-old male and female animals
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| Contributor(s) |
Simon JM, Necarsulmer JC, Cohen TJ |
| Citation(s) |
37819053 |
| |
| Submission date |
Oct 21, 2022 |
| Last update date |
Oct 24, 2023 |
| Contact name |
Jeremy Simon |
| E-mail(s) |
jsimon@ds.dfci.harvard.edu, jeremy_simon@med.unc.edu
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Department of Data Science
|
| Street address |
450 Brookline Ave
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (20)
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| Relations |
| BioProject |
PRJNA892938 |
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