From stability to pathology: protein degradation pathways underlying synaptic proteins in neurological diseases

Synaptic function and plasticity depend on the precise control of protein abundance and turnover, governed by the balance of synthesis and degradation. This review examines the regulatory mechanisms that maintain synaptic protein stability, focusing on the ubiquitin-proteasome system, autophagy-lysosomal pathways, and related proteolytic systems. We detail how key enzymes, including E3 ligases such as Nedd4-1, Mdm2, and Parkin, and deubiquitinating enzymes like USP46 and USP8, dynamically regulate the degradation of critical synaptic components from AMPA and NMDA receptors to scaffolds like PSD-95 and SHANK3. We further explore how autophagy, including chaperone-mediated and activity-dependent forms, contributes to synaptic remodeling and quality control. Crucially, dysfunction of synaptic degradation pathways is a common thread in neurodevelopmental and neurodegenerative disorders. We summarize evidence linking proteostatic malfunction to the pathogenesis of Alzheimer's disease (through impaired clearance of Aβ and tau), Parkinson's disease (via α-synuclein turnover), epilepsy, autism spectrum disorder, and ischemic injury. The review highlights how genetic mutations in degradation machinery or their synaptic targets converge to disrupt synaptic integrity and neural circuit function. By integrating findings from basic neurobiology and disease models, this review underscores the central importance of synaptic proteostasis and aims to identify critical regulatory molecules that retain potentials for diagnostic biomarkers and therapeutic targets for neurological diseases.