DRPLA Mechanism and Counter-System Framework

Dentatorubral-pallidoluysian atrophy (DRPLA) is caused by a pathogenic CAG expansion in ATN1, but the intermediate molecular state linking mutant ATN1 production to neuronal and synaptic dysfunction remains incompletely resolved. This work presents an evidence-graded operational framework separating the DRPLA disease process into distinct states: ATN1 CAG expansion, mutant RNA, full-length atrophin-1, processed protein forms, nuclear localization and retention, biologically relevant nuclear burden, nuclear dysfunction, neuronal and synaptic dysfunction, network disturbance, and structural and clinical outcomes. The framework introduces A0 as an explicitly unresolved bridge variable: the measurable nuclear-localized ATN1 form or ATN1-related activity that predicts early neuronal dysfunction beyond total ATN1 abundance. A0 is not presented as a discovered molecule or validated biomarker. It is a falsifiable operational hypothesis to be tested against competing candidates, including nuclear full-length ATN1, the approximately 120 kDa nuclear fragment, soluble nuclear fragment populations, defined ATN1 protein complexes, and dynamic nuclear-retention measures. The deposit includes an evidence register, canonical mechanism map, operational measurement specification, four falsifiable hypotheses, a minimum decisive experiment, intervention-response logic, validity controls, a machine-readable data schema, and a companion guide for external scientific review and laboratory application. The framework was developed using the operational grammar of the Planck-Operational System (POS): separate states, define ordered transitions, isolate intervention operators, predeclare invalidity conditions, log intermediate outcomes, compare against references, and retain or reject links according to predefined evidence and falsification rules. POS physical variables and Planck-normalized equations are not used as biological measurements. Status: Complete draft for external scientific assessment. Not experimentally or clinically validated. This record contains the main scientific framework and a separate scientific-review companion document. AI-assisted tools were used for literature organization, drafting support, structural synthesis, and consistency review. The named author retains responsibility for the framework, interpretations, limitations, and deposited content. https://www.change.org/p/support-research-to-cure-drpla?