C9orf72 ALS-FTD: recent evidence for dysregulation of the autophagy-lysosome pathway at multiple levels.

ABSTRACT

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two clinically distinct classes of neurodegenerative disorders. Yet, they share a range of genetic, cellular, and molecular features. Hexanucleotide repeat expansions (HREs) in the C9orf72 gene and the accumulation of toxic protein aggregates in the nervous systems of the affected individuals are among such common features. Though the mechanisms by which HREs cause toxicity is not clear, the toxic gain of function due to transcribed HRE RNA or dipeptide repeat proteins (DPRs) produced by repeat-associated non-AUG translation together with a reduction in C9orf72 expression are proposed as the contributing factors for disease pathogenesis in ALS and FTD. In addition, several recent studies point toward alterations in protein homeostasis as one of the root causes of the disease pathogenesis. In this review, we discuss the effects of the C9orf72 HRE in the autophagy-lysosome pathway based on various recent findings. We suggest that dysfunction of the autophagy-lysosome pathway synergizes with toxicity from C9orf72 repeat RNA and DPRs to drive disease pathogenesis.Abbreviation ALP autophagy-lysosome pathway; ALS amyotrophic lateral sclerosis; AMPK AMP-activated protein kinase; ATG autophagy-related; ASO antisense oligonucleotide; C9orf72 C9orf72-SMCR8 complex subunit; DENN differentially expressed in normal and neoplastic cells; DPR dipeptide repeat protein; EIF2A/eIF2α eukaryotic translation initiation factor 2A; ER endoplasmic reticulum; FTD frontotemporal dementia; GAP GTPase-activating protein; GEF guanine nucleotide exchange factor; HRE hexanucleotide repeat expansion; iPSC induced pluripotent stem cell; ISR integrated stress response; M6PR mannose-6-phosphate receptor, cation dependent; MAP1LC3/LC3 microtubule associated protein 1 light chain 3; MN motor neuron; MTORC1 mechanistic target of rapamycin kinase complex 1; ND neurodegenerative disorder; RAN repeat-associated non-ATG; RB1CC1/FIP200 RB1 inducible coiled-coil 1; SLC66A1/PQLC2 solute carrier family 66 member 1; SMCR8 SMCR8-C9orf72 complex subunit; SQSTM1/p62 sequestosome 1; STX17 syntaxin 17; TARDBP/TDP-43 TAR DNA binding protein; TBK1 TANK binding kinase 1; TFEB transcription factor EB; ULK1 unc-51 like autophagy activating kinase 1; UPS ubiquitin-proteasome system; WDR41 WD repeat domain 41.