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Review
. 2021 Nov;17(11):3306-3322.
doi: 10.1080/15548627.2021.1872189. Epub 2021 Feb 26.

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

Jimmy Beckers  1   2 , Arun Kumar Tharkeshwar  1   2 , Philip Van Damme  1   2   3
Affiliations
Review

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

Jimmy Beckers et al. Autophagy. 2021 Nov.

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.

Keywords: Amyotrophic lateral sclerosis (ALS); autophagy; axonal transport; c9orf72; dipeptide repeat protein (DPR); frontotemporal dementia (FTD); lysosome; smcr8; wdr41.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.
Overview of the autophagy pathway. (1) Bioenergetic stress caused by limited nutrient availability relieves the ULK1 complex from MTORC1 inhibition and activates the ULK1 complex through AMPK. (2) Upon initiation, the ULK1 complex translocates to omegasomes where it activates PtdIns 3-kinase complex to produce PtdIns3P and aided by the ATG12–ATG5-ATG16L1-containing complex matures to form a phagophore. (3) Expansion of the phagophore coincides with the cargo recruitment (such as aggregates, organelles) by autophagy receptors, after which the phagophore closes to form an autophagosome. (4) Retrograde trafficking of the autophagosomes facilitates their fusion with late endosomes/lysosomes converting them to autolysosomes. (5) These autolysosomes contain acid hydrolases that degrade their contents. (6) Finally, permeases present in the autolysosomal membrane mediate the diffusion of nutrients to the cytoplasm where they are re-utilized during anabolic cellular activities. Abbreviations: AMBRA1: autophagy and beclin 1 regulator 1; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BECN1: beclin 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; NRBF2: nuclear receptor binding factor 2; PtdIns3K: phosphatidylinositol 3-kinase catalytic subunit type 3; RB1CC1/FIP200: RB1 inducible coiled-coil 1; ULK1: unc-51 like autophagy activating kinase 1
Figure 2.
Figure 2.
Overview of dysregulations in the autophagy-lysosome pathway in C9orf72 ALS-FTD. Reduced C9orf72 protein levels and toxic DPRs impact the ALP at multiple levels. Autophagy-related processes that are affected in C9orf72 ALS-FTD are indicated in red while cellular hallmarks are depicted in orange. Abbreviations: DPR: dipeptide repeat protein; M6PR: mannose-6-phosphate receptor, cation dependent; MTORC1: mechanistic target of rapamycin kinase complex 1; RRAG: Ras related GTP binding; RAN: repeat-associated non-AUG; SLC66A1/PQLC2: solute carrier family 66 member 1; SMCR8SMCR8-C9orf72 complex subunit; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1; WDR41: WD repeat domain 41
Figure 3.
Figure 3.
Synergistic pathogenesis of C9orf72 disease mechanisms. Toxic HRE gain-of-function disease mechanisms (repeat RNA toxicity and DPR production) work together with C9orf72-mediated autophagy impairment and result in the aggregation of DPR and TARDBP proteins. These DPR inclusions influence a variety of homeostatic and disease mechanisms, resulting in a vicious feedback cycle. Abbreviations: DPR: dipeptide repeat protein; ISR: integrated stress response; LOF: loss-of-function; p-EIF2A: phosphorylated eukaryotic translation initiation factor 2A
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Grants and funding

The authors are supported by grants from KU Leuven (C1 - C14-17-107), Opening the Future Fund (KU Leuven), the Fund for Scientific Research Flanders (FWO-Flanders), the ALS Liga Belgium, the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek” and the “Valéry Perrier Race against ALS Fund”, the Alzheimer Research Foundation (SAO-FRA 2017/023), the Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research (VIND 135043), Flanders Innovation & Enterpreneurship (IWT grants Project MinE and iPSCAF), the Belgian National Lottery, the Latran Foundation, the European Union’s Horizon 2020 research and innovation programme (755094), the European Union’s ERA-Netfor Research Programmes on Rare Diseases (INTEGRALS). PVD holds a senior clinical investigatorship of FWO-Vlaanderen and is supported through the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders. Jimmy Beckers is a PhD fellow at FWO-Vlaanderen(11A2321N).