Mutations in hnRNP A1 drive neurodegeneration and alternative RNA splicing of neuronal gene targets
Bibliographic record
Abstract
RNA binding protein dysfunction is a pathogenic feature of multiple neurological diseases, including multiple sclerosis (MS). Neurodegeneration (the loss of, or damage to neurons and axons) is the primary driver of disease progression in MS. Herein, we utilized a novel, neuron-specific model of neurodegeneration by transducing primary mouse neurons with mutant forms of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) identified from MS patients, including one within the M9-nuclear localization sequence of hnRNP A1 (A1(P275S)) and a second in the prion-like domain of hnRNP A1 (A1(F263S)) to test the hypothesis that neuronal hnRNP A1 dysfunction drives neurodegeneration in MS. Examination of hnRNP A1 localization in neurons revealed an increase in nucleocytoplasmic mislocalization in neurons transduced with A1(P275S), but not A1(F263S). Yet, both A1(F263S) and A1(P275S) induced neurodegeneration evidenced by significant reductions in total neurite length and complexity and an increase in FluoroJade-C neuronal cell body staining. RNA sequencing and differential alternative splicing analysis of mutant-expressing neurons revealed dramatic changes in alternative RNA splicing of transcripts critical to neuronal function. Further, amyloid precursor protein ( APP ), a marker for neurodegeneration in MS, showed differential splicing in mutant-expressing neurons, which was confirmed in MS brains with hnRNP A1 dysfunction. Overall, we have identified that hnRNP A1 plays a complex role in neuronal function and regulation by mediating the alternative splicing of neuron-specific transcripts. When neuronal hnRNP A1 function is impaired, as in disease, resultant dysfunction propagates through multiple pathways that may influence the progression of neurodegeneration in MS. • RNA binding protein dysfunction is a feature of neurodegeneration in neurologic disease, including multiple sclerosis. • Somatic mutations in the RBP hnRNP A1 were identified from MS patients but their impact on neurodegeneration is unclear. • Neuronal expression of two MS-derived mutations in hnRNP A1 alter splicing of neuronal mRNAs leading to neurodegeneration. • Dysfunctional RNA binding proteins, including hnRNP A1, can alter splicing and induce neurodegeneration in neurologic disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".