ZFYVE27 (protrudin) is a key regulator of neuronal membrane trafficking and endoplasmic reticulum (ER) organization. As a FYVE-family protein, ZFYVE27 promotes axonal elongation and neuronal polarization primarily through RAB11-dependent vesicular trafficking 1. The protein functions as a peripheral membrane protein that oligomerizes into dimers/tetramers, with this oligomerization being essential for neurite extension 1. ZFYVE27 acts as a molecular adapter facilitating interactions between KIF5A motor proteins and ER-resident proteins including VAPA and VAPB, contributing to neuronal transport processes 2. Additionally, ZFYVE27 regulates ER morphogenesis by controlling the sheet-to-tubule balance and functions as a tethering factor at membrane contact sites between organelles 2. Clinically, ZFYVE27 mutations are associated with hereditary spastic paraplegia (SPG33), a progressive neurodegenerative disorder characterized by lower-limb spasticity and weakness 3. Protrudin-deficient mice exhibit depression-like behavior, hyperactivity, and cognitive deficits, suggesting broader neuropsychiatric roles beyond HSP pathology 4. Emerging evidence links ZFYVE27 variants to sarcopenia susceptibility in skeletal muscle 5, while Mendelian randomization studies suggest elevated ZFYVE27 levels may reduce pericarditis risk 6. HSP-associated mutations likely cause neurodegeneration through toxic gain-of-function rather than simple loss-of-function mechanisms.