Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43.

Overview

1. Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
2. Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3. Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
4. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

Abstract

Prion-like domain (PrLD)–mediated aggregation and concomitant dysfunction of the essential RNA-binding protein transactive response (TAR) DNA-binding protein of 43 kilodaltons (TDP-43) is a common feature of multiple debilitating neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). However, shortened TDP-43 (sTDP-43) splice isoforms where the PrLD is largely replaced by an 18-residue carboxyl-terminal tail also contribute to ALS pathophysiology and are enriched in motor neurons. Curiously, despite lacking most of the PrLD, sTDP-43 exhibits pronounced insolubility in cells and tissue of patients with ALS. Here, we establish that the short, isoform-specific carboxyl-terminal tail of sTDP-43 confers high aggregation propensity, which is encoded by two clusters of steric zippers, and can be mitigated by short RNA chaperones. Disrupting these zippers enhances sTDP-43 solubility at the pure protein level and in neurons. Notably, these steric zippers, rather than a predicted nuclear export signal in the carboxyl-terminal tail, drive cytoplasmic mislocalization and aggregation of sTDP-43 in neurons. Thus, we define the sequence-encoded determinants of aberrant sTDP-43 assembly and provide mechanistic insights into sTDP-43 disease pathology.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• doi:10.5061/dryad.ffbg79d93 — at Dryad; found in “Data, code, and materials availability:”

Data, code, and materials availability

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. Plasmids generated in this study will be made readily available to the scientific community. All requests will be honored in a timely manner. All tabulated data underlying the figures are deposited at Dryad (https://doi.org/10.5061/dryad.ffbg79d93) (89). This paper does not report original code.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 7 MeSH terms, 17 funders, 89 references, 2 RRIDs.

Cite

This paper

Copley, K. E., Dykstra, M. M., Miller, M. R., Linsenmeier, M., Lai, L., Wang, Y., Chang, Y.-W., Barmada, S. J., & Shorter, J. (2026). Isoform-specific steric zippers drive aberrant assembly and mislocalization of shortened TDP-43. Science advances, 12(26), eady0256. https://doi.org/10.1126/sciadv.ady0256

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1186/s13024-026-00944-2

TDP-43: [GU]-ardian of the transcriptome.

Journal: Molecular neurodegeneration

In common: other condition, cellular / molecular, 37 references

[2] doi:10.1016/j.nbd.2026.107475

Human TDP-43 expression worsens FTD-related phenotypes in progranulin-insufficient mice.

Journal: Neurobiology of disease

In common: cellular / molecular, 8 references

[3] doi:10.1038/s43587-026-01166-3

Therapeutic targeting of the conserved region within the low-complexity domain of TDP-43 is neuroprotective and extends survival in amyotrophic lateral sclerosis mice.

Journal: Nature aging

In common: other condition, 6 references

[4] doi:10.1038/s41467-026-77016-y

YTHDC1 functions as a molecular chaperone to suppress ALS-linked hnRNPA1 mutants from aggregation.

Journal: Nature communications

In common: other condition, cellular / molecular, 3 references

[5] doi:10.1186/s40478-026-02341-8 [code]

Intrathecal (G<sub>4</sub>C<sub>2</sub>)<sub>149</sub> delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.

Journal: Acta neuropathologica communications

In common: other condition, cellular / molecular, 3 references

[6] doi:10.1021/acs.jmedchem.6c01882

Selective Brain-Penetrant TTBK1 Inhibitors Modulate TDP-43 Pathology and Rescue Cognitive Deficits in a Mouse Model of TDP-43 Proteinopathy.

Journal: Journal of medicinal chemistry

In common: cellular / molecular, 3 references

[7] doi:10.1038/s41593-026-02348-3

Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.

Journal: Nature neuroscience

In common: cellular / molecular, 3 references

[8] doi:10.1038/s41593-026-02300-5 [code]

Integrated single-cell and spatial transcriptomic profiling in ALS uncovers peripheral-to-central immune infiltration and reprogramming.

Journal: Nature neuroscience

In common: other condition, cellular / molecular, 2 references

[9] doi:10.1016/j.cell.2026.05.047 [code]

An emergent disease-associated motor neuron state precedes cell death in ALS.

Journal: Cell

In common: other condition, cellular / molecular, 2 references

[10] doi:10.1186/s12916-026-04948-z [code]

Putative glymphatic dysfunction links extracellular fluid dysregulation to white matter degeneration and clinical impairment in amyotrophic lateral sclerosis.

Journal: BMC medicine

In common: other condition, 2 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.