Mapping and characterizing ALS-linked TDP-43 protein-protein interactions
Why this work is in the frame
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Bibliographic record
Abstract
Amyotrophic lateral sclerosis (ALS) is a moto-neuron disorder in which an RNA-binding protein, TDP-43, mislocalizes and pathologically accumulates from its normal nuclear locale to the cytosol. Given that the subcellular localization and expression of TDP-43 is tightly regulated and affected by its protein-protein interactions (PPIs), we posit that identifying novel interactors of wild-type and mutant TDP-43 could reveal insight into networks involved in driving ALS pathogenesis. Using CRISPR/Cas9, our lab has generated knockin cell lines expressing GFP-tagged wildtype (WT) and an ALS-causing mutant (Q331K) TDP-43, in the endogenous TARDBP locus (coding for TDP-43). We have shown that the Q331K mutation causes loss-of-function and mislocalization of TDP-43. We have performed immunoprecipitation-mass spectrometry (IP-MS) on these cell lines to elucidate interactors of WT- and Q331K, TDP-43. Our data has shown that there is an overall loss of interactors with the Q331K mutation. We have analyzed these data using bioinformatic approaches to shortlist and validate 14 candidates. From this, 4 interactors have shown robust interaction with TDP-43 via IP-western blot. We are using cellular and biochemical assays to assess the effects of knockdown and overexpression of these top 4 hits on TDP-43 localization and loss-of-function. Using this unbiased approach, we will identify TDP-43 PPIs and characterize their roles in cellular functions in the context of ALS, giving insight into pathways involved in driving neurodegeneration.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it