Lysosomal biophysics in CLN3 disease: Connecting membrane transport, molecular homeostasis, and tissue dysfunction

CLN3 disease (CLN3 Batten disease) is a lysosomal neurodegenerative disorder characterized by early retinal degeneration and progressive neurological dysfunction, yet the mechanisms connecting CLN3-dependent membrane physiology to selective cellular and tissue vulnerability remain unresolved. This review integrates current evidence across four experimentally separable scales: membrane biophysics, molecular and organellar homeostasis, cell-specific function, and tissue pathology. Direct electrophysiological studies support a luminal pH-sensitive CLN3-dependent lysosomal chloride conductance associated, in tested systems, with changes in luminal chloride, pH, cathepsin activity, and protein degradation. Independently, CLN3 deficiency disrupts glycerophosphodiester clearance, phospholipid and cholesterol handling, cation-independent mannose 6-phosphate receptor trafficking, hydrolase delivery, and autophagic lysosomal reformation. These organellar abnormalities coexist with distinct phenotypes in retinal pigment epithelium, neurons, microglia, astrocytes, and brain endothelial cells, together with retinal, neural-circuit, and myelin abnormalities at the tissue level. Current evidence does not establish a universal chloride-first or storage-first cascade; instead, it supports interacting CLN3-dependent modules whose causal ordering may vary by cell type, model, and disease stage. We therefore propose a multiscale mechanistic framework that links measurable lysosomal physical variables to molecular homeostasis, cell-specific function, and tissue vulnerability while preserving the distinction between direct evidence and mechanistic inference. This framework defines testable priorities for causal ordering, rescue experiments, and mechanism-matched target engagement in CLN3 disease.