Loss of proteostasis and early-onset neurodegeneration in Down Syndrome: from mechanisms to interventions

Down syndrome (DS), caused by trisomy 21, is the most prevalent genetic condition associated with accelerated aging and near-universal development of early-onset Alzheimer’s disease (AD). Beyond gene-dosage imbalance, trisomy 21 induces widespread transcriptional, metabolic, and proteomic remodeling that establishes a chronic state of proteotoxic and oxidative stress from early development. Increasing evidence identifies DS as a disorder of proteostasis network failure, in which sustained translational pressure, redox disequilibrium, and degradation pathway insufficiency progressively erode cellular resilience. In the DS brain, persistent endoplasmic reticulum stress with PERK-dominant signaling, mitochondrial dysfunction characterized by oxidative phosphorylation deficits and excessive reactive oxygen species production, and impaired antioxidant responses create a highly vulnerable intracellular environment. Concomitantly, degradation systems become compromised: proteasomal catalytic activity declines, ubiquitin-dependent signaling is remodeled, and chronic mTOR hyperactivation suppresses autophagic and mitophagic flux. The coordinated impairment of the ubiquitin–proteasome system and autophagy establish a feed-forward cycle of proteotoxic accumulation and redox amplification. Within this framework, Alzheimer-like neuropathology in DS emerges not solely from amyloid precursor protein triplication but as the late manifestation of decades-long proteostasis exhaustion. Therapeutic strategies aimed at restoring global proteostasis and redox balance may therefore represent a more effective systems-level approach to mitigating neurodegeneration in DS.