The Role of Rab Proteins in Parkinson's Disease Synaptopathy

Abstract

In patients affected by Parkinson's disease (PD), the most common neurodegenerative movement disorder, the brain is characterized by the loss of dopaminergic neurons in the nigrostriatal system, leading to dyshomeostasis of the basal ganglia network activity that is linked to motility dysfunction. PD mostly arises as an age-associated sporadic disease, but several genetic forms also exist. Compelling evidence supports that synaptic damage and dysfunction characterize the very early phases of either sporadic or genetic forms of PD and that this early PD synaptopathy drives retrograde terminal-to-cell body degeneration, culminating in neuronal loss. The Ras-associated binding protein (Rab) family of small GTPases, which is involved in the maintenance of neuronal vesicular trafficking, synaptic architecture and function in the central nervous system, has recently emerged among the major players in PD synaptopathy. In this manuscript, we provide an overview of the main findings supporting the involvement of Rabs in either sporadic or genetic PD pathophysiology, and we highlight how Rab alterations participate in the onset of early synaptic damage and dysfunction.

Keywords: GBA1; LRRK2; Parkinson’s disease; Rab proteins; alpha-synuclein; autophagy; synaptopathy.

Figure 1

The cartoon summarizes the Rabs involved in the modulation of synaptic function in physiological conditions (A) and in aSyn aggregation and spreading (B).

Figure 2

The cartoon summarizes the Rabs participating in the different phases of macroautophagy, from autophagosome formation to its fusion with the lysosome.