Targeting lipid droplets in FUS-linked amyotrophic lateral sclerosis mitigates neuronal and astrocytic lipotoxicity
Bibliographic record
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, muscle atrophy and systemic energy imbalance. Increasing evidence suggests a metabolic shift in ALS from glucose metabolism toward fatty acid utilization; however, the downstream consequences of this reprogramming on disease progression and neuropathology remain poorly defined. We investigated neurometabolic changes in ALS using in vitro and in vivo models of familial ALS expressing the human fused in sarcoma variant R521G (hFUSR521G), along with post-mortem spinal cord tissue from ALS-FUS cases. A combination of unbiased quantitative metabolomic profiling, immunolabelling, and biochemical and molecular approaches were employed. Mass spectrometry of cortical tissue from hFUSR521G mice and littermates revealed a significant increase in acylcarnitine moieties, key substrates used in mitochondrial β-oxidation and cellular energy production. Complementary cytohistological analyses in hFUSR521G mice demonstrated increased lipid droplets (LDs) and peroxidized lipids in both neurons and astrocytes, consistent with our post-mortem findings in spinal cords of individuals carrying FUS R495X or K510E mutations. Arimoclomol, previously shown to ameliorate behavioural phenotypes in this ALS mouse model, was found to enhance lipid metabolism and reduce lipotoxicity in hFUSR521G mice and in cultured neurons and astrocytes expressing FUS R521G. Mechanistically, arimoclomol enhanced LD-mitochondrial contacts and stimulated mitochondrial β-oxidation-dependent lipid catabolism under both basal and pro-inflammatory conditions. This effect was abrogated by etomoxir, an irreversible inhibitor of carnitine palmitoyltransferase I (CPT1), the rate-limiting enzyme of the carnitine shuttle, highlighting a CPT1-dependent mechanism for lipid mobilization. Together, these findings reveal a previously unrecognized role for mitochondrial lipid metabolism in ALS pathogenesis and identify a therapeutic pathway for mitigating the cytotoxic consequences of lipid and acylcarnitine accumulation in FUS-associated ALS.
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How this classification was reachedexpand
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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".