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.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson Disease

“…This variant is also an eQTL for RAB9B gene in cells (cultured fibroblasts), a non-brain tissue. Several studies have shown a relationship between the Ras analog in brain genes (RAB) in the pathogenesis of PD [49,50]. Although none of these studies directly mention RAB9B, they did investigate the role of RAB9A, a gene paralog of RAB9B.…”

The Role of Rab Proteins in Mitophagy: Insights into Neurodegenerative Diseases

“…In this frame, an unbalanced orchestration of such pathways has severe detrimental effects in neurons, where specific sub-cellular compartments rely on proper mitochondrial activity, such as synaptic terminals. Recently, a clear role for Rab proteins has been unveiled in synaptic damage, which characterizes the very early stages of both sporadic and familial PD [ 115 ]. Indeed, this early synaptopathy drives retrograde terminal-to-cell body degeneration, leading to neuronal cell death.…”

“…Indeed, this early synaptopathy drives retrograde terminal-to-cell body degeneration, leading to neuronal cell death. Specifically, Rab proteins were found to be involved in the maintenance of synaptic architecture and function, and their dysregulation is implicated in synaptic alterations concerning α-synuclein and LRRK2 pathology [ 115 ]. Oxidative phosphorylation is the main process that powers neuronal activities [ 116 ]; thus, the lack of functional mitochondria in the right place, namely, at the active synapse, can impair several pathways, such as neurotransmitter release, calcium buffering, and the action potential propagation.…”

Bringing synapses into focus: Recent advances in synaptic imaging and mass-spectrometry for studying synaptopathy

“…Therefore, when synaptic dysfunction occurs it can induce catastrophic consequences for essential neurological processes. Synaptopathies, characterized by pathological synaptic dysfunction and loss, are now recognized as a common component of many neurodegenerative disorders such as Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinson’s disease (PD), and Huntington’s disease (HD) ( Kerrigan and Randall, 2013 ; Nishimura and Arias, 2021 ; Bellucci et al, 2022 ). Synaptopathy may arise in various ways: for example, mislocalization and aggregation of disease-associated proteins can affect synaptic function leading to breakdown ( Lim and Yue, 2015 ; Wang et al, 2017 ; Taoufik et al, 2018 ).…”