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Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia
- Source :
- J Clin Invest
- Publication Year :
- 2020
- Publisher :
- American Society for Clinical Investigation, 2020.
-
Abstract
- No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell-derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.
- Subjects :
- Male
0301 basic medicine
Pathology
medicine.medical_specialty
Induced Pluripotent Stem Cells
Stathmin
Disease
TARDBP
Progressive supranuclear palsy
03 medical and health sciences
0302 clinical medicine
mental disorders
Humans
Medicine
Dementia
biology
business.industry
nutritional and metabolic diseases
RNA
General Medicine
Human brain
Middle Aged
medicine.disease
Frontal Lobe
nervous system diseases
DNA-Binding Proteins
030104 developmental biology
medicine.anatomical_structure
Frontotemporal Dementia
030220 oncology & carcinogenesis
Mutation
Commentary
biology.protein
Female
business
Biomarkers
Frontotemporal dementia
Subjects
Details
- ISSN :
- 15588238 and 00219738
- Volume :
- 130
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation
- Accession number :
- edsair.doi.dedup.....483d15a88c83d9536657eb1ffebc8c77