FGF2 Affects Parkinson’s Disease-Associated Molecular Networks Through Exosomal Rab8b/Rab31

Abstract

Ras-associated binding (Rab) proteins are small GTPases that regulate the trafficking of membrane components during endocytosis and exocytosis including the release of extracellular vesicles (EVs). Parkinson's disease (PD) is one of the most prevalent neurodegenerative disorder in the elderly population, where pathological proteins such as alpha-synuclein (α-Syn) are transmitted in EVs from one neuron to another neuron and ultimately across brain regions, thereby facilitating the spreading of pathology. We recently demonstrated fibroblast growth factor-2 (FGF2) to enhance the release of EVs and delineated the proteomic signature of FGF2-triggered EVs in cultured primary hippocampal neurons. Out of 235 significantly upregulated proteins, we found that FGF2 specifically enriched EVs for the two Rab family members Rab8b and Rab31. Consequently, we investigated the interactions of Rab8b and Rab31 using a network analysis approach in order to estimate the global influence of their enrichment in EVs. To achieve this, we have demarcated a protein-protein interaction network (PPiN) for these Rabs and identified the proteins associated with PD in various cellular components of the central nervous system (CNS), in different brain regions, and in the enteric nervous system (ENS). A total of 126 direct or indirect interactions were reported for two Rab candidates, out of which 114 are Rab8b interactions and 54 are Rab31 interactions, ultimately resulting in an individual interaction score (IS) of 90.48 and 42.86%, respectively. Conclusively, these results for the first time demonstrate the relevance of FGF2-induced Rab-enrichment in EVs and its potential to regulate PD pathophysiology.

Proteomic characterization of secretory granules in dopaminergic neurons indicates chromogranin/secretogranin-mediated protein processing impairment in Parkinson’s disease

“…Recent proteome studies indicate that FGF2 facilitated the extracellular vesicle (EV)-mediated alpha-synuclein (a-Syn) transmission by upregulated Ras-associated binding proteins (Rabs) and a-Syn interacting proteins in PD and Lewy body pathology (LBP). In the current study, although Rabs were not significantly altered, we observed increased levels of FGF1 and one of the a-Syn interacting proteins ribosomal protein Rsp14, which contributes to mitochondrial fragmentation and energy failure [ 39 , 40 ]. Brekk et al [ 28 ] identified an aberrant accumulation of α-Syn specific to Scg2 positive SGs in multiple brain regions in the aged mice, accompanied by the loss of synaptic proteins PSD-95 and TUBB3.…”

Exosomes as cell-derivative carriers in the diagnosis and treatment of central nervous system diseases

“…Furthermore, an investigation was carried out to determine the influence of these Rab proteins in the enrichment of proteins connected with Parkinson's disease in the CNS, various parts of the brain and in the enteric nervous system through a protein-protein interaction network. A majority of the interactions were obtained for the two Rab proteins, thus demonstrating their relevance in the regulation of the exosomal proteins and its capability to manage the pathophysiology of Parkinson's disease [137].…”

“…Another, study aimed to identify certain serum exosomes as biomarkers of various stages of Parkinson's by analysing the exosomal proteins using mass spectrometry. The proteonomic analysis revealed a dwindled level for certain proteins such as complement C1q and protein immunoglobulin lambda variable 1-33 (IGLV1-33) cluster-33 in Parkinson's which could be an indicator to the pathophysiological mechanism of Parkinson's (137).…”

Parkinson’s disease causality and heterogeneity: a proteogenomic view

“…66 As seen in GBA+ patients, reduced DLK1 levels in idiopathic patients may suggest neurodegeneration. Lower levels of RAB31, a small GTPase involved in exosome biogenesis 67 and potentially in alpha-synuclein spreading in Parkinson's disease 68 were observed, too. RIPK2, a LRRK2 substrate, is lower in idiopathic patients, which matches the fact that LRRK2 deficiency leads to reduced activation of RIPK2.…”