Department of Neuroscience, Mayo Clinic, Mangurian Research Building, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL, USA.
Acta Neuropathol Commun. 2022 Jul 25;10(1):107. doi: 10.1186/s40478-022-01408-6.
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.
额颞叶变性伴 TDP-43 病理学（FTLD-TDP）是一种主要影响额极和/或颞极的神经退行性疾病。然而，越来越多的证据表明，小脑对 FTLD-TDP 的生化、认知和行为变化有贡献。为了评估 FTLD-TDP 中小脑 TDP-43 的表达和功能，我们分析了 95 例 FTLD-TDP 病例和 25 例非神经疾病对照者小脑组织中 TDP-43 蛋白水平和 TDP-43 靶标 STMN2 的剪接。FTLD-TDP 病例的小脑可溶性 TDP-43 减少，但未观察到不溶性 TDP-43 的伴随增加。TDP-43 功能障碍的指标——截断的 STMN2 转录本在 FTLD-TDP 病例的小脑组织中升高，并与 TDP-43 水平呈负相关。此外，小脑 TDP-43 水平较低与疾病发病年龄较小有关。我们为 FTLD-TDP 中小脑 TDP-43 功能丧失提供了证据，支持对这一研究不足的脑区进行进一步研究。
