| Popis: |
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene\ud is the most common genetic defect associated with amyotrophic lateral sclerosis\ud (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a\ud resulting loss of C9orf72 protein function has been suggested as a possible\ud pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin\ud and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum\ud and hippocampus, indicating possible autophagy deficits in these patients. In a\ud recent study, we investigated this possibility by reducing expression of C9orf72 in cell\ud lines and primary neurons and found that C9orf72 regulates the initiation of\ud autophagy. C9orf72 interacts with Rab1a, preferentially in its GTP-bound state, as\ud well as the ULK1 autophagy initiation complex. As an effector of Rab1a, C9orf72\ud controls the Rab1a-dependent trafficking of the ULK1 initiation complex prior to\ud autophagosome formation. In line with this function, C9orf72 depletion in cell lines\ud and primary neurons caused the accumulation of p62/sequestosome-1-positive\ud inclusions. In support of a role in disease pathogenesis, C9ALS/FTD patient-derived\ud iNeurons showed markedly reduced levels of autophagy.\ud In this Commentary we summarise recent findings supporting the key role of C9orf72\ud in Rab GTPase-dependent regulation of autophagy and discuss autophagy\ud dysregulation as a pathogenic mechanism in ALS/FTD. |
