Myopathic aggregation-prone variants in the TDP-43 prion-like domain: genetics paving the way

Topic: Brain proteins, microglia and lab models

While neuropathological and genetic studies have established the crucial involvement of TDP-43 proteinopathy in the pathogenesis of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and related neurodegenerative disorders, multiple studies have described the presence of TDP-43 inclusions in muscular disorders, including inclusion body myositis but also other related rimmed vacuole myopathies. In addition, TAR DNA-binding protein-43 (TDP-43) has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury. However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing. In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology. We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity. Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of 'multisystem proteinopathy'.

Key findings

• In addition, TAR DNA-binding protein-43 (TDP-43) has been reported to be essential in normal muscle physiology as it is implicated in the formation of so-called amyloid-like myogranules during normal muscle regeneration after injury.
• However, genetic evidence supporting a primary role for TDP-43 proteinopathy in muscle disease has been missing.
• In the present review we highlight recent landmark discoveries linking novel pathogenic TDP-43 variants [p.(W385IfsX10) and p.(G376V)] within the prion-like domain with unusual aggregation-propensity and muscle rather than neuronal pathology.
• We discuss these studies in the context of known TDP-43-related pathways in ALS/FTD pathogenesis and show how they challenge some widely accepted views such as ALS as a pure neurogenic presynaptic neuromuscular disease and the direct correlation between TDP-43 aggregation-propensity and neurotoxicity.
• Finally, we discuss TDP-43 as part of a growing list of RNA-binding proteins including hnRNPA2B1 and hnRNPA1 as genetic causes of myopathies and relate this to the idea of 'multisystem proteinopathy'.

Why it matters

This review highlights newly discovered pathogenic TDP-43 variants within the prion-like domain that are linked to muscle rather than neuronal pathology, and discusses how these findings challenge accepted views about TDP-43 aggregation and neurotoxicity. It is a review of genetic discoveries and does not test any treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1093/brain/awaf076
• PubMed: 40036368
• Original source →
• Free full text: Ghent University Academic Bibliography (Ghent University) →

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

@article{pereira2025-40036368,
  author  = {Pereira, Pedro Ervilha and De Bleecker, Jan and Bogaert, Elke and Dermaut, Bart},
  title   = {{Myopathic aggregation-prone variants in the TDP-43 prion-like domain: genetics paving the way}},
  journal = {Brain},
  year    = {2025},
  doi     = {10.1093/brain/awaf076},
  pmid    = {40036368},
  url     = {https://doi.org/10.1093/brain/awaf076}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 30.

• 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
• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis Nature genetics · 2009-09-06 · usefulness score 64/100 · How common it is
• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A Nature · 2022-02-23 · usefulness score 64/100 · Lewy body dementia
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A Nature · 2022-02-23 · usefulness score 64/100 · 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
• 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 repression of nonconserved cryptic exons is compromised in ALS-FTD Science (New York, N.Y.) · 2015-08-01 · usefulness score 57/100 · Lewy body dementia
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death Neuron · 2019-03-07 · usefulness score 56/100 · Lewy body dementia

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• The seeds of neurodegeneration: prion-like spreading in ALS Cell · 2011-10-01 · usefulness score 53/100
• Limbic-predominant Age-related TDP-43 Encephalopathy and Distinct Longitudinal Profiles of Domain-specific Literacy Alzheimer disease and associated disorders · 2020 · usefulness score 64/100
• Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain Nature Communications · 2025-11-26 · usefulness score 52/100
• Fluorescence Lifetime-Based FRET Biosensors for Monitoring N Terminal Domain-Dependent Interactions of TDP-43 in Living Cells: A Novel Approach for ALS and FTD Drug Discovery ACS Chemical Neuroscience · 2025-06-10 · usefulness score 38/100
• ALS-associated mutations reveal a conserved C-terminal self-assembly module in the TDP-43 low-complexity domain bioRxiv · 2026-10-12 · usefulness score 16/100
• TDP-43 in amyotrophic lateral sclerosis - is it a prion disease? European journal of neurology · 2015-05 · usefulness score 38/100

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