@article{118417d42bf54043a09e0fe2fa54cc59,
title = "Evidence of cerebellar TDP-43 loss of function in FTLD-TDP",
abstract = "Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is a neurodegenerative disease primarily affecting the frontal and/or temporal cortices. However, a growing body of evidence suggests that the cerebellum contributes to biochemical, cognitive, and behavioral changes in FTLD-TDP. To evaluate cerebellar TDP-43 expression and function in FTLD-TDP, we analyzed TDP-43 protein levels and the splicing of a TDP-43 target, STMN2, in the cerebellum of 95 FTLD-TDP cases and 25 non-neurological disease controls. Soluble TDP-43 was decreased in the cerebellum of FTLD-TDP cases but a concomitant increase in insoluble TDP-43 was not seen. Truncated STMN2 transcripts, an indicator of TDP-43 dysfunction, were elevated in the cerebellum of FTLD-TDP cases and inversely associated with TDP-43 levels. Additionally, lower cerebellar TDP-43 associated with a younger age at disease onset. We provide evidence of TDP-43 loss of function in the cerebellum in FTLD-TDP, supporting further investigation into this understudied brain region.",
keywords = "Cerebellum, Frontotemporal lobar degeneration, Stathmin-2, TDP-43",
author = "Sarah Pickles and Gendron, {Tania F.} and Yuka Koike and Mei Yue and Yuping Song and Kachergus, {Jennifer M.} and J. Shi and Michael DeTure and Thompson, {E. Aubrey} and Bj{\"o}rn Oskarsson and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Petersen, {Ronald C.} and Wszolek, {Zbigniew K.} and Josephs, {Keith A.} and Dickson, {Dennis W.} and Leonard Petrucelli and Cook, {Casey N.} and Mercedes Prudencio",
note = "Funding Information: MP serves as a consultant for Target ALS. LP serves as a consultant for Expansion Therapeutics. LP has licensing agreements for frontotemporal dementia mouse models and antibodies. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, a gift from the Donald G. and Jodi P. Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation. ZKW serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206 and BHV3241-301), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.001 and VGL101-01.002) grants. ZKW serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. BO serves as a consultant for Columbia University/Tsumura Inc, MediciNova, and Mitsubishi and have research grants from Columbia University/Tsumura Inc, Biogen, MediciNova, Cytokinetics, Mitsubishi, Calico, and Target ALS. Funding Information: This work was supported by NIH grants R35NS097273 (LP), U54NS123743 (LP, MP), P01NS084974 (LP), RF1NS120992 (MP, KAJ), R01AG37491 (KAJ), R01AG063780 (CNC), and the Robert Packard Center for ALS Research at Johns Hopkins (L.P.). YK is supported by Milton Safenowitz Postdoctoral Fellowship Program from the Amyotrophic Lateral Sclerosis Association (21-PDF-582). SP is supported by a BrightFocus ADR Grant (A2020279F). ZKW is supported by a gift from the Donald G. and Jodi P. Herringa Family. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1186/s40478-022-01408-6",
language = "English (US)",
volume = "10",
journal = "Acta Neuropathologica Communications",
issn = "2051-5960",
publisher = "BioMed Central",
number = "1",
}