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Review
. 2021 Nov 8;22(21):12087.
doi: 10.3390/ijms222112087.

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson's Disease

José Ángel Martínez-Menárguez  1 , Emma Martínez-Alonso  1 , Mireia Cara-Esteban  2 , Mónica Tomás  2
Affiliations
Review

Focus on the Small GTPase Rab1: A Key Player in the Pathogenesis of Parkinson's Disease

José Ángel Martínez-Menárguez et al. Int J Mol Sci. .

Abstract

Parkinson's disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α-σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies.

Keywords: GTPases; Golgi fragmentation; LRRK2; Parkinson’s disease; Rab1; autophagy; secretory pathway; α-synuclein.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Regulation of GTP–GTP cycle of Rab GTPases by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), GDP dissociation inhibitor (GDI), and GDI displacement factors (GDF). Membrane-associated GTP-bound Rabs are able to interact with effectors.
Figure 2
Figure 2
Main effectors of Rab1 involved in secretory traffic (A) and autophagy (B).
Figure 3
Figure 3
Overview of the roles and regulation of Rab1 and how it may be affected in PD. Activity and association with membranes of Rab1 are regulated by TRAPPIII (a guanine nucleotide exchange factor, GEF), TBC1D120 (a GTPase-activating protein, GAP), PRA1 (a GDI displacement factor, GDF), and αGDI (a GDP dissociation inhibitor, GDI). This activity is also regulated by the PD-related protein LRRK2. Rab1 regulates the early steps of the secretory pathway and autophagy through many effectors (see the full text for details). In addition, it regulates Hrr25, a member of the casein kinase 1 family, which also regulates these pathways. The expression of mutant forms of α-synuclein or overexpression of the wild type impair the secretory pathway, resulting in the activation of the UPR, the fragmentation of the Golgi ribbon, and the failure of the lysosomal route. These PD-associated alterations also affect autophagy. PD-related mutants of LRRK2 may enhance the activity of this GTPase, impairing secretory and autophagy pathways. Unbalanced secretory/autophagic/endolysosomal routes may lead to the formation of Lewy bodies.
Figure 4
Figure 4
Rab1 overexpression reduces α-synuclein aggregates. These aggregates were induced in neuron-like differentiated PC12 cells by treatment with METH as a model of PD. Cells overexpressing Rab1-GFP have a reduced number of aggregates.
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References

    1. Balestrino R., Schapira A. Parkinson disease. Eur. J. Neurol. 2020;27:27–42. doi: 10.1111/ene.14108. - DOI - PubMed
    1. Kalia L.V., Lang A. Evolving basic, pathological and clinical concepts in PD. Nat. Rev. Neurol. 2016;12:65–66. doi: 10.1038/nrneurol.2015.249. - DOI - PubMed
    1. Visanji N.P., Mollenhauer B., Beach T.G., Adler C.H., Coffey C.S., Kopil C.M., Dave K.D., Foroud T., Chahine L., Jennings D. The Systemic Synuclein Sampling Study: Toward a biomarker for Parkinson’s disease. Biomark. Med. 2017;11:359–368. doi: 10.2217/bmm-2016-0366. - DOI - PubMed
    1. Bordelon Y., Keener A. Parkinsonism. Semin. Neurol. 2016;36:330–334. doi: 10.1055/s-0036-1585097. - DOI - PubMed
    1. Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J. Neurochem. 2016;139:318–324. doi: 10.1111/jnc.13691. - DOI - PubMed

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