TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord

Topic: Brain proteins, microglia and lab models

This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson's disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer's disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex.

@article{feneberg2025-40826370,
  author  = {Feneberg, Emily and Thompson, Alexander G. and Charles, Philip D. and Vendrell, Iolanda and Kessler, Benedikt M. and Fischer, Román and Ansorge, Olaf and Gray, Elizabeth E. and others},
  title   = {{TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord}},
  journal = {Acta Neuropathologica Communications},
  year    = {2025},
  doi     = {10.1186/s40478-025-02084-y},
  pmid    = {40826370},
  url     = {https://doi.org/10.1186/s40478-025-02084-y}
}

Key findings

• This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson's disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer's disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions.
• RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction.
• Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found.
• No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions.
• Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex.

Why it matters

Comparing spinal cord and cerebral cortex from ALS donors, this study found different protein profiles associated with TDP-43 inclusions in each region, with RNA/DNA metabolic processes affected in spinal cord and mitochondrial and synaptic pathways in cortex. No significant increase in TDP-43 interacting proteins was found in either fraction.

Study details

• Participants16
• Evidence strengthLow

Read the original

• DOI: 10.1186/s40478-025-02084-y
• PubMed: 40826370
• Original source →
• Free full text: Acta Neuropathologica Communications →

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

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