Basic Science and Pathogenesis

Background: Circadian rhythm disorder is not only a characteristic of neurodegenerative diseases but may participate in driving the pathological development in early stages of these diseases. Transactive response DNA-binding protein of 43 kDa (TDP-43) knockdown and its pathological aggregation are associated with severe neurodegenerative diseases such as amyotrophic lateral sclerosis.

Methods: C57BL/6 mice were sleep deprived and sarcrificed at ZT0, ZT6, ZT12, and ZT18 and detected by Western blots. M17 cells infected with Lenti/TDP-43_KO and then performed to RNA sequencing, and detected by qPCR to verify the RNA-seq results. Mice were intracerebroventricular injected with AAV/shTDP-43 and detected by Western blots and qPCR. HEK-293T cells were transfected with TDP-43, TDP-43_KO or treated with MG132 or cycoheximide and performed to immunoprecipitation and detected by Western blots.

Results: Herein we found that TDP-43 expression exhibited rhythmic patterns and regulated the expression of multiple circadian genes such as BMAL1, CLOCK, CRY1, and PER2, particularly affecting the mRNA and protein levels of BMAL1; knockdown of TDP-43 in mice brain also changed the autonomous circadian wheel behavior, cognitive and balance ability of the animal. Further, we discovered that TDP-43 could at least regulate the expression and alternative splicing of USP13, thereby affecting the protein level of USP13 and the ubiquitin-mediated degradation of BMAL1 and regulated the AMPK signaling pathway, resulted in changing the cellular glucose uptake and ATP production.

Conclusion: Our findings would expand the understanding of the role of TDP-43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidences supporting the interaction between circadian rhythm disruption and neurodegeneration.