The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two extremes of a neurodegenerative disease spectrum characterised by overlapping genetic, clinical, and neuropathological features. This review covers the intricate relationship between both ALS and FTD and defects in the autophagy and endolysosomal pathway as recent evidence has pointed towards alterations in these pathways as being a root cause of disease pathogenesis. Here, we review the current knowledge on the interplay between ALS/FTD and lysosomebased proteostasis pathways and carefully asses the steps of the autophagy and endolysosomal pathways that are impaired by ALS or FTDcausing variants. Finally, we present a comprehensive overview of therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating the impact of these devastating diseases. Through this review, we aim to enhance the understanding of the pathophysiological mechanisms involving autophagy and/or the endolysosomal system that underlie the ALS-FTD spectrum and underscore the necessity for specific therapeutic approaches that target these shared vulnerabilities.

Keywords: Amyotrophic lateral sclerosis (ALS); autophagosome; autophagy; endolysosome; endosome; frontotemporal dementia (FTD); lysosome; neurodegeneration.

Figure 1.

Schematic overview of the various signs that link ALS and FTD to defects in the autophagy and endolysosomal pathways. Abbreviations: ALS: amyotrophic lateral sclerosis; FTD: frontotemporal dementia; TDP-43: TAR DNA binding protein; TMEM106B: transmembrane protein 106B.

Figure 2.

Comprehensive overview of the endolysosomal and autophagy pathways and the specific parts of these pathways that are affected by ALS -or FTD-related genes and risk factors. Various gene variants causative for ALS and/or FTD (depicted in red) have an impact on the endolysosomal and autophagy pathway at different levels (depicted in purple). Abbreviations: AMPK: AMP-activated protein kinase; ATG: autophagy-related; LAMP1/2: lysosomal associated membrane protein 1/2; MAP1LC3-II/LC3-II: microtubule associated protein 1 light chain 3 (lipid modified); M6PR: mannose-6-phosphate receptor; mTORC1: mechanistic target of rapamycin kinase complex 1; NBR1: NBR1 Autophagy Cargo Receptor; OPTN: optineurin; PI3KC3: phosphatidylinositol 3-kinase catalytic subunit type 3; SQSTM1/p62: sequestome 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

Figure 3.

Therapies currently being tested in clinical trials for ALS and/or FTD. Abbreviations: AMPK: AMP-activated protein kinase; ATF4: activating transcription factor 4; eIF2B: eukaryotic translation initiation factor 2B; GADD34: growth arrest and DNA damage-inducible protein; GSK-3β: glycogen synthase kinase-3β; MAP2K/MEK: mitogen-activated protein kinase; mTORC1: mechanistic target of rapamycin kinase complex 1; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.