Neurodegenerative Proteinopathy-Specific Dysregulation of Iron Homeostasis in the Human Brain
Bibliographic record
Abstract
Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are neurodegenerative diseases involving distinct protein pathology but are commonly characterized by pronounced iron deposition in vulnerable brain regions early affected in the disease-course. Neurotoxic iron burden has been linked to regions of protein pathology, but the function of iron dysregulation in disease pathogenesis remains unknown. We hypothesized that differences in cellular iron homeostasis correlate with protein cytopathology and disease progression. Using PSP and MSA post-mortem human brains we performed the first comprehensive cellular characterization of pathological iron deposition in early vulnerable regions utilizing a unique histology method that combines iron staining with immunolabelling. We further explored underlying molecular pathways by transcriptional analysis and multiplex immunolabelling of associated players in the same brain regions. Our study reveals distinct cellular vulnerability patterns of iron deposition in PSP and MSA, especially in relation to protein cytopathologies. In PSP, we identify tau-associated astrocytic iron accumulation, dysregulation of neuronal oxygen homeostasis, and dysregulation of tau pathology-associated Neurodegeneration with Brain Iron Accumulation (NBIA) genes as novel pathophysiology that may contribute to disease aetiology or early pathogenesis. In MSA, we describe microglial iron accumulation and dysregulation of nigral oxygen homeostasis which may contribute to disease toxicity; but further, we identify cellular vulnerability patterns to iron deposition as a novel neuropathological characteristic that predicts MSA clinical subtypes, suggesting iron dysregulation may contribute to different disease progression. Deconstructing the commonly observed iron accumulation at a new level of detail, we reveal novel correlations between pathological iron deposition and different pathologic features of the diseases which further reinforce the role of iron dysregulation in disease pathogeneses. Importantly however, our research suggest iron-associated pathogenic mechanisms to be distinct in a proteinopathy-specific manner. Our findings describe key cellular pathophysiology that are fundamental for fine delineation of iron functions in neurodegenerative disease pathogeneses which altogether will inform efforts in iron chelation therapies at the disease- and cellular-specific levels.
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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) | 0.000 | 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 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".