Syntaxin-4 at the Crossroads of Synaptic Plasticity and Neurodegeneration: From Molecular Mechanisms to Biomarker and Therapeutic Potential.

Abstract

Syntaxin-4 (Stx4), a member of the Qa-SNARE protein family, is a pivotal regulator of membrane trafficking. Stx4 is predominantly localized at the postsynaptic membrane of neurons and in glial cells, where it is essential for synaptic plasticity and the maintenance of neuronal homeostasis. Stx4 facilitates the activity-dependent exocytosis of glutamatergic receptors, thereby governing the balance between Long-Term Potentiation (LTP) and Long-Term Depression (LTD). Emerging evidence suggests that dysregulation of Stx4 is intricately linked to the pathogenesis of neurodegenerative diseases. In Alzheimer's disease, Stx4 is involved in synaptic dysfunction and cognitive impairment through its interactions with amyloid-β (Aβ) and tau pathologies, affecting receptor recruitment at dendritic spines. In Parkinson's Disease (PD), Stx4 contributes to α-synuclein proteostasis, dopaminergic signaling, neuroinflammation, and the maintenance of blood-brain barrier integrity. While its presence in cerebrospinal fluid highlights its potential as a candidate biomarker for these diseases, further validation is required to establish clinical utility. This review summarizes current mechanistic insights into Stx4's multifaceted roles in the neurodegenerative disorders and explores the therapeutic prospects of targeting Stx4-mediated pathways due to its translational potential.