Rab27b: A Modulator of Lysosomal Function and Alpha-Synuclein Clearance in Parkinson's Disease

Lysosomes are often referred to as the cell's recycling center, serving as the terminal degradative compartments of the endolysosomal and autophagic systems, through which cellular waste is broken down (Lloyd-Evans and Haslett, 2016). Extracellular cargo and cell-surface proteins enter the degradation pathway via endocytosis and phagocytosis through early to late endosomes before fusing with lysosomes. Cytosolic proteins are cleared by autophagy (“eating oneself”), in which autophagosomes deliver materials to lysosomes. Regardless of the pathway, final degradation depends on the lysosome's acidic environment, which activates hydrolytic enzymes like cathepsin D, a lysosomal enzyme involved in the degradation of proteins and the activation of precursor enzymes (Lloyd-Evans and Haslett, 2016). This system of waste trafficking and clearance is particularly important for neurons, which rely on it to maintain their axons (Lloyd-Evans and Haslett, 2016; Underwood et al., 2020; Nixon and Rubinsztein, 2024; Scholz et al., 2025). Consequently, impaired lysosomal function is a central contributor to the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease (PD) as well as the neurodegenerative lysosomal storage disorders Gaucher disease, Batten disease, and Niemann–Pick disease (Lloyd-Evans and Haslett, 2016; Do et al., 2019; Prieto Huarcaya et al., 2022). PD is characterized by the intracellular accumulation of misfolded α-Syn in Lewy bodies within midbrain dopaminergic neurons, leading to their degeneration, which causes motor symptoms. As clearance of α-Syn is mediated by the autophagy–lysosome pathway, defects in this system drive disease progression by impairing protein clearance and promoting neuroinflammation, synaptic dysfunction, and ultimately, neuronal cell death (Lloyd-Evans and Haslett, 2016; Nixon and Rubinsztein, 2024; Jiao et al., 2025; Xie et al., 2025). The importance of the autophagosome–lysosome system in α-Syn clearance is supported by genetic evidence. Mutations in genes associated with … Correspondence should be addressed to Rafael A. Badell-Grau at rbadellgrau{at}health.ucsd.edu.