Evidence of cerebellar TDP-43 loss of function in FTLD-TDP
Sarah Pickles, Tania F. Gendron, Yuka Koike, Mei Yue, Yuping Song, Jennifer M. Kachergus, Jing Shi, Michael DeTure, E. Aubrey Thompson, Björn Oskarsson, Neill R. Graff‐Radford, Bradley F. Boeve, Ronald C. Petersen, Zbigniew K. Wszołek, Keith A. Josephs, Dennis W. Dickson, Leonard Petrucelli, Casey Cook, Mercedes Prudencio
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.