期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 11, 页码 6080-6092出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI139741
关键词
-
资金
- NINDS, NIH [R35NS097273, P01NS084974, R21NS084528, R01NS088689, P01NS099114, R01AG037491, P50AG016574, U01AG006786, U01AG045390]
- National Institute on Aging [R56AG055824]
- Department of Defense [ALSRP AL130125]
- Mayo Clinic Foundation
- Association of Frontotemporal Dementia (AFTD)
- Amyotrophic Lateral Sclerosis Association
- Robert Packard Center for ALS Research at Johns Hopkins
- Target ALS
- Canadian Institute of Health Research
- UK Medical Research Council
- Motor Neuron Disease Association
- Rosetrees Foundation
- National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre
- Alzheimers Research UK
- UK Dementia Research Institute from DRI Ltd. - UK Medical Research Council
- Alzheimers Society
- Intramural Research Program, NINDS, NIH
- ALS Association [15-LGCA-234]
- Tow Foundation
- MRC [MR/P007023/1, MR/N013255/1, MR/S006508/1, UKDRI-4003] Funding Source: UKRI
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据