The Enigmatic Role of C9ORF72 in Autophagy

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the loss of motor neurons resulting in a progressive and irreversible muscular paralysis. Advances in large-scale genetics and genomics have revealed intronic hexanucleotide repeat expansions in the gene encoding C9ORF72 as a main genetic cause of ALS and frontotemporal dementia (FTD), the second most common cause of early-onset dementia after Alzheimer's disease. Novel insights regarding the underlying pathogenic mechanisms of C9ORF72 seem to suggest a synergy of loss and gain of toxic function during disease. C9ORF72, thus far, has been found to be involved in homeostatic cellular pathways, such as actin dynamics, regulation of membrane trafficking, and macroautophagy. All these pathways have been found compromised in the pathogenesis of ALS. In this review, we aim to summarize recent findings on the function of C9ORF72, particularly in the macroautophagy pathway, hinting at a requirement to maintain the fine balance of macroautophagy to prevent neurodegeneration.

Keywords: ALS; C9ORF72; FTD; autophagy; macroautophagy.

Figure 1

Pathogenic roles of C9ORF72 in ALS and FTD. (A) Pathogenic GGGGCC repeat extensions [in the figure showed as (G4C2)n] can inhibit the transcription of endogenous C9ORF72, resulting in (B) diminished levels of C9ORF72 protein (loss of function); (C) (G4C2)n C9ORF72 can be both aberrantly sense and antisense transcribed to (G4C2)n C9RNA; (D) RNA foci containing these (G4C2)n C9RNA are found in the nucleus of C9ALS/FTD patients, sequestering RNA-binding proteins, such as TDP-43, and FUS, increasing the RNA processing dysfunction in ALS (gain of a RNA toxic function). (E) Also, (G4C2)n C9RNA are Repeat Associated Non-ATG (RAN) translated in toxic dipeptide repeat proteins (DPRs), contributing to the gain of a protein toxic function through (F) disruption of nuclear/cytosol transport by DRPs binding nuclear pore proteins; (G) DRPs are present in cytosolic protein inclusions in affected neurons, together with SQSTM1/p62, poly-ubiquitined proteins (Ub) and unfolded/misfolded (U/M) proteins; (H) bind to and inhibit the proteasome; (I) bind to and contributes to mitochondria dysfunction; and (J) cause DNA damage.

Figure 2

Physiological roles of C9ORF72 in macroautophagy. In (A) normal C9ORF72 was shown to act as an effector for Rab1 GTPases, mediating the traffic of ULK1/2 initiation complex to the phagophore. Also, Rab1/C9ORF72 could acts downstream recruiting C9ORF72 in complex with SMCR8 and WDR41 as a GEF for Rab39b, contributing to the localization of activated ULK1/2 initiation complex in the place to start the phagophore formation. TBK1 phosphorylates SMCR8 protein, promoting the binding of C9ORF72 to Rab39b, Rab39b then activates the ULK1 complex, promoting its traffic to the phagophore. (B). By interacting with SQSTM1/p62 (p62) and possibly via Rab39b, C9ORF72 in complex with SMCR8 and WDR41 could contribute to the delivery of poly-ubiquitinated (Ub), unfolded/misfolded (U/M) protein aggregates to the autophagosome (selective macroautophagy). (C) C9ORF72 was showed to interact to several Rabs, and could be contributing to membrane trafficking to the nascent phagophore (with Rab11) and with the fusion of autophagosome with the lysosome (with Rab7). (D) The complex composed by C9ORF72 and SMCR8 could modulate mTORC1 nutrient sensing when localized to the lysosome, promoting the translocation of TFEB to the nucleus after mitigation of mTORC1 signaling, increasing the lysosomal biogenesis and ATG genes transcription. “?” is added for the mechanisms that still need further experimental proofs.