TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity

Topic: Brain proteins, microglia and lab models

Non-amyloid, ubiquitinated cytoplasmic inclusions containing TDP-43 and its C-terminal fragments are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). Importantly, TDP-43 mutations are linked to sporadic and non-SOD1 familial ALS. However, TDP-43 is not the only protein in disease-associated inclusions, and whether TDP-43 misfolds or is merely sequestered by other aggregated components is unclear. Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS and FTLD-U patients [corrected] . The C-terminal domain of TDP-43 is critical for spontaneous aggregation. Several ALS-linked TDP-43 mutations within this domain (Q331K, M337V, Q343R, N345K, R361S, and N390D) increase the number of TDP-43 aggregates and promote toxicity in vivo. Importantly, mutations that promote toxicity in vivo accelerate aggregation of pure TDP-43 in vitro. Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations.

@article{johnson2009-19465477,
  author  = {Johnson, B. S. and Snead, D. and Lee, J. J. and McCaffery, J. M. and Shorter, J. and Gitler, A. D.},
  title   = {{TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity}},
  journal = {The Journal of biological chemistry},
  year    = {2009},
  doi     = {10.1074/jbc.m109.010264},
  pmid    = {19465477},
  url     = {https://doi.org/10.1074/jbc.m109.010264}
}

Key findings

• Here, we report that, in the absence of other components, TDP-43 spontaneously forms aggregates bearing remarkable ultrastructural similarities to TDP-43 deposits in degenerating neurons of ALS and FTLD-U patients [corrected] .
• The C-terminal domain of TDP-43 is critical for spontaneous aggregation.
• Several ALS-linked TDP-43 mutations within this domain (Q331K, M337V, Q343R, N345K, R361S, and N390D) increase the number of TDP-43 aggregates and promote toxicity in vivo.
• Importantly, mutations that promote toxicity in vivo accelerate aggregation of pure TDP-43 in vitro.
• Thus, TDP-43 is intrinsically aggregation-prone, and its propensity for toxic misfolding trajectories is accentuated by specific ALS-linked mutations.

Why it matters

This laboratory study found that the TDP-43 protein clumps on its own and that ALS-linked mutations in a specific part of the protein increase clumping and toxicity. This helps explain how TDP-43 may cause disease but does not test a treatment or cure.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.m109.010264
• PubMed: 19465477
• Original source →
• Free full text: Journal of Biological Chemistry →

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Studies this one cites

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

• 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
• Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations Annals of neurology · 2007-05-01 · usefulness score 63/100 · Brain tissue and pathology
• 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
• Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease Nature medicine · 1998-11-01 · usefulness score 58/100 · 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
• Alpha-synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity Nature genetics · 2009-02-01 · usefulness score 54/100 · Risk factors

Later studies that cite this one

43 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• 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
• Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies Science (New York, N.Y.) · 2023-03-16 · usefulness score 60/100 · Brain tissue and pathology
• Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis Neuron · 2013-08-01 · usefulness score 58/100 · Lewy body dementia
• TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia The Lancet. Neurology · 2010-10-01 · usefulness score 57/100 · Lewy body dementia
• TDP-43 Pathology in Alzheimer's Disease Molecular neurodegeneration · 2021-12-20 · 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
• TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD Nature neuroscience · 2018-03-19 · usefulness score 56/100 · Brain tissue and pathology
• 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

Related studies in Lewy body dementia

• ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43 Proceedings of the National Academy of Sciences of the United States of America · 2013-02-04 · usefulness score 53/100
• Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis Nature neuroscience · 2014-03-30 · usefulness score 58/100
• Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Annals of neurology · 2008-07-01 · usefulness score 54/100
• Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis The Journal of neuroscience : the official journal of the Society for Neuroscience · 2010-01-01 · usefulness score 54/100
• TDP-43 dysregulation of polyadenylation site selection is a defining feature of RNA misprocessing in amyotrophic lateral sclerosis and frontotemporal dementia Journal of Clinical Investigation · 2025-06-01 · usefulness score 51/100
• Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis Frontiers in molecular neuroscience · 2019-02-14 · usefulness score 50/100

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• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation 2017 · Lewy body dementia
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