The progress in C9orf72 research: ALS/FTD pathogenesis, functions and structure

ABSTRACT

The hexanucleotide repeat (GGGGCC) expansion in C9orf72 is accounted for a large proportion of the genetic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The hypotheses of how the massive G4C2 repeats in C9orf72 destroy the neurons and lead to ALS/FTD are raised and improving. As a multirole player, C9orf72 exerts critical roles in many cellular processes, including autophagy, membrane trafficking, immune response, and so on. Notably, the partners of C9orf72, through which C9orf72 participates in the cell activities, have been identified. Notably, the structures of the C9orf72-SMCR8-WDR41 complex shed light on its activity as GTPase activating proteins (GAP). In this manuscript, we reviewed the latest research progress in the C9orf72-mediated ALS/FTD, the physiological functions of C9orf72, and the putative function models of C9orf72/C9orf72-containing complex.

KEYWORDS:

• DENN domain
• autophagy
• membrane trafficking
• neurodegenerative
• GAP
• GEF
• C9orf72
• SMCR8
• WDR41
• lysosome
• mTOR

Acknowledgments

This work was supported by the National Key R&D Program of China grant 2017YFA0506300 (L. K.), 2018YFC1004601 (S.Q.), and NSFC grants 32071214 (Q. S.), 31770820 (L. K.).

Disclosure statement

The authors declare that they have no conflicts of interest with the contents of this article.

Additional information

Funding

This work was supported by the National Key R&D Program of China [2017YFA0506300]; NSFC [31770820]; NSFC [32071214]; National Key R&D Program of China [2018YFC1004601].