Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses

Topic: Brain proteins, microglia and lab models

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share common genes and pathomechanisms and are referred to as the ALS-FTD spectrum. A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions. Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility. This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form. Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs). Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.

Key findings

• A hallmark of ALS-FTD pathology is the abnormal aggregation of proteins, including Cu/Zn superoxide dismutase (SOD1), transactive response DNA-binding protein 43 (TDP-43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), and dipeptide repeat proteins resulting from C9orf72 hexanucleotide expansions.
• Genetic mutations linked to ALS-FTD disrupt protein stability, phase separation, and interaction networks, promoting misfolding and insolubility.
• This review explores the molecular mechanisms underlying protein aggregation in ALS-FTD, with a particular focus on TDP-43, as it represents the main aggregated species inside pathological inclusions and can also aggregate in its wild-type form.
• Moreover, this review describes the protective mechanisms activated by the cells to prevent protein aggregation, including molecular chaperones and post-translational modifications (PTMs).
• Understanding these regulatory pathways could offer new insights into targeted interventions aimed at mitigating cell toxicity and restoring cellular function.

Why it matters

This review describes molecular mechanisms of protein aggregation in ALS-FTD, focusing on TDP-43, and the cell's protective responses such as molecular chaperones and post-translational modifications. It suggests these pathways could offer insights for future targeted interventions, but reports no treatment that has been shown to work.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.3390/cells14100680
• PubMed: 40422183
• Original source →
• Free full text: Cells →

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

@article{verde2025-40422183,
  author  = {Verde, Enza Maria and Secco, Valentina and Ghezzi, Andrea and Mandrioli, Jessica and Carra, Serena},
  title   = {{Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses}},
  journal = {Cells},
  year    = {2025},
  doi     = {10.3390/cells14100680},
  pmid    = {40422183},
  url     = {https://doi.org/10.3390/cells14100680}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 62.

• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• 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
• TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia Brain : a journal of neurology · 2016-11-01 · usefulness score 63/100 · Getting a diagnosis
• 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
• 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
• TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis The Lancet. Neurology · 2008-04-07 · usefulness score 61/100 · Lewy body dementia
• Characterizing the RNA targets and position-dependent splicing regulation by TDP-43 Nature neuroscience · 2011-02-27 · usefulness score 61/100 · Lewy body dementia
• Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice Nature · 2017-04-12 · usefulness score 61/100 · Lewy body dementia
• TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD Nature neuroscience · 2018-01-08 · usefulness score 61/100 · Lewy body dementia
• Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons Nature medicine · 2018-02-05 · usefulness score 60/100 · Lewy body dementia
• The overlap of amyotrophic lateral sclerosis and frontotemporal dementia Neurology · 2002-10-01 · usefulness score 59/100 · Getting a diagnosis
• The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS Science (New York, N.Y.) · 2013-02-07 · usefulness score 59/100 · Lewy body dementia

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• From Evasion to Collapse: The Kinetic Cascade of TDP-43 and the Failure of Proteostasis International Journal of Molecular Sciences · 2026-01-23 · usefulness score 36/100 · Brain tissue and pathology

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