TDP-43, explained — and what's being tested against it

A calm, sourced tracker of research on TDP-43, the protein that goes wrong in nearly all cases of ALS. Plain English first; the science is one tap away.

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What is TDP-43?

TDP-43 is a protein your cells make from a gene called TARDBP^[9]. Normally it lives in the cell's nucleus (its control center), where it grabs onto RNA — the working copies of genes — and helps edit them correctly.

In ALS, TDP-43 leaves the nucleus and clumps together in the surrounding cell. This was discovered in 2006^[1]. Those clumps are found in about 97% of people with ALS and about 45% of people with frontotemporal dementia (FTD)^[2]. That includes most people with ALS who have no known genetic cause.

So there are two problems: the clumps may be toxic, and the nucleus loses TDP-43's editing work. When that editing stops, some genes pick up junk pieces called cryptic exons^[4]. Two important examples:

STMN2 (stathmin-2) helps nerve fibers grow and repair. Without TDP-43, STMN2 is badly made and levels drop^[5]^[6].
UNC13A helps nerve cells pass signals across synapses. Without TDP-43 it is also mis-made, and common gene variants that raise ALS risk make this worse^[7]^[8].

Because these broken pieces show up only when TDP-43 isn't working, researchers are using them both as biomarkers (signs you can measure) and as drug targets: several drugs now in trials try to put STMN2 or UNC13A back.

Deeper dive: the molecular details

TDP-43 (TAR DNA-binding protein 43) is a 414-amino-acid heterogeneous nuclear ribonucleoprotein encoded by TARDBP on chromosome 1^[9]. It has an N-terminal domain that self-associates, two RNA-recognition motifs (RRM1, RRM2) that bind UG-rich RNA, and a C-terminal low-complexity (prion-like) domain where most disease mutations cluster^[3].

In ALS/FTLD-TDP, TDP-43 is depleted from the nucleus and forms cytoplasmic inclusions that are hyperphosphorylated, ubiquitinated and cleaved into C-terminal fragments^[1]. Dominant TARDBP mutations cause a small fraction of familial ALS^[3], showing that TDP-43 dysfunction can be causal, not just a bystander.

Loss of nuclear TDP-43 de-represses poorly conserved cryptic exons^[4]. In STMN2, a cryptic exon in intron 1 with a premature polyadenylation site produces a truncated transcript and loss of stathmin-2^[5]^[6]. In UNC13A, cryptic exon inclusion triggers nonsense-mediated decay; ALS/FTD risk SNPs in the same intron potentiate inclusion^[7]^[8]. Truncated STMN2 RNA and cryptic peptides are being explored as fluid and tissue readouts of TDP-43 loss-of-function, and antisense oligonucleotides that block the cryptic splice sites are in clinical trials (see pipeline).

The numbers "~97% of ALS / ~45% of FTD" are autopsy-based estimates summarized by Ling, Polymenidou & Cleveland (2013)^[2]. Exceptions include SOD1- and FUS-related ALS, which usually lack TDP-43 inclusions.

On this site

Pipeline — 11 programs that target TDP-43 or its downstream effects.
Trials — 17 ALS studies on ClinicalTrials.gov that explicitly mention TDP-43, TARDBP, STMN2, UNC13A or related terms.
Papers — 45 recent PubMed papers (last ~18 months).
Glossary & resources.

TDP-43, explained — and what's being tested against it

What is TDP-43?

On this site

Sources