A Proteostatic Paradigm Linking ADHD and Gambling Disorder: Autophagy Dysfunction, Blood–Brain Barrier Breakdown, and Synaptic Instability

Clinically significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and gambling disorder (GD)—estimated at 30–50%—remains inadequately explained by conventional dopamine-deficiency models. This Perspective proposes a novel "Proteostatic Paradigm" that integrates recent advances in autophagy biology, blood-brain barrier (BBB) physiology, and synaptic proteostasis to explain this clinical association mechanistically. We present a multi-stage cascade: chronic autophagic dysfunction, particularly impaired lysophagy via the TBK1-FBXO3-TMEM192-TAX1BP1 axis, triggers oxidative stress and protease activation, leading to degradation of tight junction proteins (ZO-1, occludin, Claudin-5) and subsequent BBB breakdown. This vascular disruption permits infiltration of peripheral inflammatory mediators (TNF-α, IL-1β, IL-6), establishing chronic neuroinflammation that suppresses dopaminergic signaling in frontostriatal circuits—the neurobiological substrate of ADHD symptoms. This framework generates testable predictions, including biomarker ratios (LC3B-II/Claudin-5 for autophagy-BBB coupling; RIM1/Bassoon for synaptic compensation) and suggests interventions targeting upstream mechanisms may reduce both ADHD symptoms and gambling vulnerability.