Can the mutant huntingtin gene product spread from cell to cell: Evidence from neuronal allografts in Huntington's disease patients (S15.002)
Bibliographic record
Abstract
Huntington’s disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin (mHtt)), which is thought to exert its effects in a cell-autonomous manner where degeneration occurs within individual cells that carry the aberrant gene. Here, we investigated the hypothesis that mHtt (like pathogenic protein species involved in other neurodegenerative conditions) is capable of spreading within cerebral tissue. The brains of four patients with HD who received genetically unrelated fetal neural allografts at least a decade earlier were examined post-mortem. The presence of mHtt aggregates within the grafted tissue was confirmed using an array of techniques including microscopy (brightfield, fluorescence and electron), western immunoblotting and infrared spectroscopy, and a number of different antibodies targeting different epitopes of mHtt aggregates. A number of mHtt protein aggregates were located within intracerebral allografts of striatal tissue in three of these HD patients. No grafts survived in the fourth transplant recipient. The mHtt+ aggregates were observed in the extracellular matrix of the genetically unrelated transplanted tissue while in the host brain they were localized in neurons, neuropil, extracellular matrix and blood vessels. In addition, peripheral immune cells in separate HD patients contained mHtt. There are a thus a number of non cell-autonomous mechanisms which could explain these observations including transynaptic propagation as well as hematogenous transport of mHtt, among others. In summary, we have shown, for the first time, the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brains of HD patients. These observations raise questions on the importance of non-cell autonomous mechanisms of protein spread in genetic disorders of the CNS, and further provide new targets for the development of therapeutic strategies. Supported by the International Organization of Glutaric Acidemia (IOGA) awarded to FC who is also recipient of a National Researcher career award from FRQS.
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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 | 0.000 |
| 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".