Work

Rab GTPases and the Rabopathy framework: from synaptic trafficking to neurodegeneration via LRRK2-driven pathology

Year: 2026

Type: article

Abstract: Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) show significant differences in their clinical manifestations, but they all seem to share a common upstream problem: malfunction in the membrane transport controlled by Rab GTPases. This review introduces the concept of Rabopathy, a framework that connects developmental synaptic maturation defects with late-onset protein aggregation. The LRRK2–Rab phosphorylation axis is emerging as a potential common amplifying mechanism across these disorders, with the strongest mechanistic support in PD and growing implications in AD and HD. When Rab substrates are excessively phosphorylated at specific sites, vesicular transport is impaired or arrested, leading to progressive depletion of the reserve pool of synaptic vesicles and the surface pool of receptors, and severe compromise of the autophagy-lysosome flux. The failure of distinct Rab sub-networks also produces disease-specific signatures, including Rab5-driven endosomal congestion in AD, Rab35-mediated α-synuclein secretion in PD, and Rab11/Rab7 trafficking collapse in HD. Restoration of Rab flux may be a therapeutic strategy for neurodegenerative diseases, which can be achieved through calibration of LRRK2 activity, modulation of selective Rab subtypes, and rescue of the trafficking network at the systems level.

Source: Translational Neurodegeneration

DOI: 10.1186/s40035-026-00596-8