Mitochondrial and Axonal Abnormalities Precede Disruption of the Neurofilament Network in a Model of Charcot-Marie-Tooth Disease Type 2E and Are Prevented by Heat Shock Proteins in a Mutant-Specific Fashion
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Bibliographic record
Abstract
Mutations in NEFL encoding the light neurofilament subunit (NFL) cause Charcot-Marie-Tooth disease type 2E (CMT2E), which affects both motor and sensory neurons. We expressed the disease-causing mutants NFL and NFL in motor neurons of dissociated spinal cord-dorsal root ganglia and demonstrated that they are incorporated into the preexisting neurofilament network but eventually disrupt neurofilaments without causing significant motor neuron death. Importantly, rounding of mitochondria and reduction in axonal diameter occurred before disruption of the neurofilament network, indicating that mitochondrial dysfunction contributes to the pathogenesis of CMT2E, as well as to CMT caused by mitofusin mutations. Heat shock proteins (HSPs) are involved in the formation of the neurofilament network and in protecting cells from misfolded mutant proteins. Cotransfection of HSPB1 with mutated NEFL maintained the neurofilament network, axonal diameter, and mitochondrial length in motor neurons expressing NFL, but not NFL. Conversely, HSPA1 cotransfection was effective in motor neurons expressing NFL, but not NFL. Thus, there are NFL mutant-specific differences in the ability of individual HSPs to prevent neurofilament abnormalities, reduction in axonal caliber, and disruption of mitochondrial morphology in motor neurons. These results suggest that HSP inducers have therapeutic potential for CMT2E but that their efficacy would depend on the profile of HSPs induced and the type of NEFL mutation.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| 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 it