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

Topic: Brain proteins, microglia and lab models

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.

Key findings

• 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.

Why it matters

This review covers the relationship between ALS/FTD and defects in the autophagy and endolysosomal pathway, with recent evidence pointing towards alterations in these pathways as a root cause of disease pathogenesis. It presents therapeutic strategies aimed at restoring autophagic and lysosomal function as potential avenues for mitigating these diseases.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1080/27694127.2025.2474796
• PubMed: 40395983
• Original source →
• Free full text: Autophagy Reports →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{beckers2025-40395983,
  author  = {Beckers, Jimmy and Van Damme, Philip},
  title   = {{The role of autophagy in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)}},
  journal = {Autophagy Reports},
  year    = {2025},
  doi     = {10.1080/27694127.2025.2474796},
  pmid    = {40395983},
  url     = {https://doi.org/10.1080/27694127.2025.2474796}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 46.

• Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results Nature medicine · 2024-05-14 · usefulness score 71/100 · Long-term cohort studies
• Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions Nature genetics · 2010-02-14 · usefulness score 66/100 · Risk factors
• Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis PLoS genetics · 2008-09-19 · usefulness score 65/100 · Lewy body dementia
• Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Nature · 2006-07-16 · usefulness score 64/100 · Lewy body dementia
• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD Neuron · 2011-09-21 · usefulness score 63/100 · Lewy body dementia
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature · 2011-08-21 · usefulness score 62/100 · Lewy body dementia
• Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS Neuron · 2011-09-21 · usefulness score 62/100 · Lewy body dementia
• Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Nature · 2006-07-16 · usefulness score 61/100 · Lewy body dementia
• Exome sequencing reveals VCP mutations as a cause of familial ALS Neuron · 2010-12-01 · usefulness score 61/100 · How common it is
• Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons Nature medicine · 2018-02-05 · usefulness score 60/100 · Lewy body dementia

Later studies that cite this one

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• Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy Molecules · 2026-03-10 · usefulness score 36/100 · Brain tissue and pathology

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