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, J. Shi, Michael DeTure, E. Aubrey Thompson, Björn Oskarsson, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, Zbigniew K. Wszolek, Keith A. Josephs, Dennis W Dickson, Leonard Petrucelli, Casey Cook, Mercedes Prudencio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number107
JournalActa Neuropathologica Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 2022

Keywords

  • Cerebellum
  • Frontotemporal lobar degeneration
  • Stathmin-2
  • TDP-43

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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