Abstract
Dysfunctional autophagy or ubiquitin-proteasome system (UPS) are suggested to underlie abnormal protein aggregation in neurodegenerative diseases. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS)-associated C9orf72 is implicated in autophagy, but whether it activates or inhibits autophagy is partially controversial. Here, we utilized knockdown or overexpression of C9orf72 in mouse N2a neuroblastoma cells or cultured neurons to elucidate the potential role of C9orf72 proteins in autophagy and UPS. Induction of autophagy in C9orf72 knockdown N2a cells led to decreased LC3BI to LC3BII conversion, p62 degradation, and formation of LC3-containing autophagosomes, suggesting compromised autophagy. Proteasomal activity was slightly decreased. No changes in autophagy nor proteasomal activity in C9orf72-overexpressing N2a cells were observed. However, in these cells, autophagy induction by serum starvation or rapamycin led to significantly decreased C9orf72 levels. The decreased levels of C9orf72 in serum-starved N2a cells were restored by the proteasomal inhibitor lactacystin, but not by the autophagy inhibitor bafilomycin A1 (BafA1) treatment. These data suggest that C9orf72 undergoes proteasomal degradation in N2a cells during autophagy. Lactacystin significantly elevated C9orf72 levels in N2a cells and neurons, further suggesting UPS-mediated regulation. In rapamycin and BafA1-treated neurons, C9orf72 levels were significantly increased. Altogether, these findings corroborate the previously suggested regulatory role for C9orf72 in autophagy and suggest cell type-dependent regulation of C9orf72 levels via UPS and/or autophagy.
Highlights
Frontotemporal dementia (FTD), the most common clinical phenotype of frontotemporal lobar degeneration (FTLD), is the third most common cause of early onset dementia in individuals under65 years of age [1]
Whether the C9orf72 proteins regulate the function of the ubiquitin-proteasome system (UPS) and whether they themselves are regulated by autophagy or UPS have not been studied before
The C9orf72 proteins mainly reside in the cytosol and they may be secreted [15]
Summary
Frontotemporal dementia (FTD), the most common clinical phenotype of frontotemporal lobar degeneration (FTLD), is the third most common cause of early onset dementia in individuals under. The pathological mechanisms of the HRE underlying neurodegeneration are controversial, but are suggested to involve haploinsufficiency, leading to a decreased expression of the normal C9orf gene products (loss-of-function), as well as formation and accumulation of toxic RNA foci and dipeptide repeat (DPR) proteins that are directly generated from the expanded repeat (gain-of-toxic-function) [7,8,9,10]. Even though there is substantial evidence indicating that the main pathological mechanisms underlying HRE-associated FTD and ALS are related to gain-of-toxic-function, haploinsufficiency has been suggested to contribute to the disease pathogenesis. Autophagy and the ubiquitin-proteasome system (UPS) are essential pathways controlling proteostasis in cells, especially during stress conditions, such as those prevailing in diseased brain These pathways are in charge of degrading unfolded, misfolded, or aggregated proteins. We have elucidated the yet-unknown regulation of the C9orf protein itself through autophagy and UPS-mediated protein degradation
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