Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration

Topic: Brain proteins, microglia and lab models

Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid-liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid-liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration.

Key findings

• These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role.
• We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted.

Why it matters

This review examines the conflicting evidence on whether TDP-43 phosphorylation drives disease progression or serves a neuroprotective role in conditions including frontotemporal dementia. It highlights unresolved questions about the regulation of TDP-43 phosphorylation and does not report a treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1186/s13024-025-00839-8
• PubMed: 40340943
• Original source →
• Free full text: Molecular Neurodegeneration →

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

@article{kellett2025-40340943,
  author  = {Kellett, Elise A. and Bademosi, Adekunle T. and Walker, Adam K.},
  title   = {{Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration}},
  journal = {Molecular Neurodegeneration},
  year    = {2025},
  doi     = {10.1186/s13024-025-00839-8},
  pmid    = {40340943},
  url     = {https://doi.org/10.1186/s13024-025-00839-8}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here. Showing 12 of 40.

• 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
• TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis Science · 2008-02-28 · usefulness score 64/100 · Disease mechanisms
• 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
• Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration Nature neuroscience · 2019-01-14 · usefulness score 62/100 · Lewy body dementia
• Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases Acta neuropathologica · 2007-07-25 · usefulness score 59/100 · How common it is
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity Nature medicine · 2016-06-27 · usefulness score 58/100 · Lewy body dementia
• Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity The EMBO journal · 2017-08-08 · 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
• TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration Human molecular genetics · 2010-04-15 · usefulness score 56/100 · Lewy body dementia

Later studies that cite this one

3 studies in the alzhub library list this one in their references.

• Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis Brain · 2026-03-09 · usefulness score 43/100 · Brain tissue and pathology
• TDP-43: [GU]-ardian of the transcriptome Molecular Neurodegeneration · 2026-05-14 · usefulness score 42/100 · Brain tissue and pathology
• Chemical and Molecular Strategies in Restoring Autophagic Flux in TDP-43 Proteinopathy Molecules · 2026-03-10 · usefulness score 36/100 · Brain tissue and pathology

Related studies in Brain tissue and pathology

• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses Cells · 2025-05-08 · usefulness score 44/100
• Elucidation of Molecular Mechanisms of Lipid-Altered Cytotoxicity of TDP-43 Fibrils ACS Chemical Neuroscience · 2026-01-29 · usefulness score 38/100
• Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies Journal of neurochemistry · 2016-06-15 · usefulness score 51/100
• TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2015-04-01 · usefulness score 50/100
• A quantitative cell-based reporter links TDP-43 aggregation and dysfunction to define pathogenic mechanisms PLoS Biology · 2026-03-24 · usefulness score 42/100
• Proteomics of the temporal cortex in semantic dementia reveals brain-region specific molecular pathology and regulation of the TDP-43-ANXA11 interactome Acta Neuropathologica Communications · 2025-07-25 · usefulness score 41/100

Also tagged “mice”

1,150 studies in the library carry the topic tag “mice”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,150 tagged studies.

• Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo Neuron · 2005-12-01 · usefulness score 56/100 · Disease mechanisms
• Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice Alzheimer's research & therapy · 2022-04-26 · usefulness score 53/100 · Caregiving
• Galectin-3, a rising star in modulating microglia activation under conditions of neurodegeneration Cell death & disease · 2022-07-20 · usefulness score 49/100 · TREM2 and immune genetics

Similar studies

• Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation 2022 · Brain tissue and pathology
• Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies 2009 · Brain tissue and pathology
• The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies 2020 · Lewy body dementia
• DCPS modulates TDP-43-linked neurodegeneration through P-body-mediated RNA decay 2026 · Brain tissue and pathology
• TDP-43 pathology triggers neuroinflammation and cognitive impairment by inducing microglial necroptosis 2026 · Brain tissue and pathology
• Functional Significance of TDP-43 Mutations in Disease 2015 · Brain tissue and pathology

More on Brain tissue and pathology

• A review that covers this ground Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases Nature reviews. Molecular cell biology · 2024-08-06 · usefulness score 60/100
• Newest in this subject Inflammatory biomarker candidates in dementia with Lewy bodies: diagnostic classification, clinical associations, and survival Research Square · 2026-11-01 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject TMEM106B C-Terminal fragment aggregation exacerbates α-synuclein and TDP-43 proteinopathy phenotypes bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100

See all studies in Brain tissue and pathology →