Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice A new light for treatment of TARDBP/TDP-43 proteinopathies

摘要

The administration of rapamycin, an MTOR-dependent autophagy activator, for the treatment of neurode-generative diseases has been tested in several animal models. Thus, whether autophagy activation would lead to the clearance of abnormal accumulation of aggregated proteins in neurodegen-erative diseases is worthy of exploration. We have recently shown that rapamycin administration at the early pathological stage of a mouse model with frontotem-poral lobar dementia (FTLD-U) characterized with cytoplasmic TARDBP/ TDP-43 (+)/ubiquitin(+) inclusions (UBIs) in the diseased neurons could rescue the learning/memory deficiency and the abnormal motor function disorder of the mice. This was accompanied by a decreased level of CASP3/caspase-3 and a reduction of the neuronal loss in the mouse forehead. Moreover, autophagy activation at a late pathological stage also could improve motor function, which was accompanied by a reduction of the TARDBP(+) UBIs. This study has set the principal for therapy of neurode-generative diseases with the TARDBP protein, i.e., amyotrophic lateral sclerosis (ALS)-TDP and FTLD-TDP43, with the use of autophagy activators.