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

Martı́nez-Menárguez, José A.; Martínez‐Alonso, Emma; Cara-Esteban, Mireia; Tomàs, Mariona

doi:10.3390/ijms222112087

Cited by 11 publications

(5 citation statements)

References 219 publications

(248 reference statements)

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“…The reason why these neurons are particularly affected in PD remains unclear. Golgi fragmentation as a result of defective Rab1‐dependent ER‐to‐Golgi transport may significantly alter homeostasis of dopaminergic neurons triggering cell death (Martínez‐Menárguez et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

Cara‐Esteban,

Marín,

Martínez‐Alonso

et al. 2023

Microscopy Res & Technique

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Since gastrointestinal disorders are early consequences of Parkinson's disease (PD), this disease is clearly not restricted to the central nervous system (CNS), but also significantly affects the enteric nervous system (ENS). Large aggregates of the protein α‐synuclein forming Lewy bodies, the prototypical cytopathological marker of this disease, have been observed in enteric nervous plexuses. However, their value in early prognosis is controversial. The Golgi complex (GC) of nigral neurons appears fragmented in Parkinson's disease, a characteristic common in most neurodegenerative diseases. In addition, the distribution and levels of regulatory proteins such as Rabs and SNAREs are altered, suggesting that PD is a membrane traffic‐related pathology. Whether the GC of enteric dopaminergic neurons is affected by the disease has not yet been analyzed. In the present study, dopaminergic neurons in colon nervous plexuses behave as nigral neurons in a hemiparkinsonian rat model based on the injection of the toxin 6‐OHDA. Their GCs are fragmented, and some regulatory proteins' distribution and expression levels are altered. The putative mechanisms of the transmission of the neurotoxin to the ENS are discussed. Our results support the possibility that GC structure and the level of some proteins, especially syntaxin 5, could be helpful as early indicators of the disease.Research Highlights The Golgi complexes of enteric dopaminergic neurons appear fragmented in a Parkinson's disease rat model. Our results support the hypothesis that the Golgi complex structure and levels of Rab1 and syntaxin 5 could be helpful as early indicators of the disease.

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Section: Discussionmentioning

confidence: 99%

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

Cara‐Esteban,

Marín,

Martínez‐Alonso

et al. 2023

Microscopy Res & Technique

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“…Rab1b is required for vesicle transport between the ER and the Golgi [28]. Given the unbalance of Rab1b expression and compaction of the Golgi in cells lacking sacsin, Rab1b association with Golgi or ER was characterized by measuring the PCC of ectopically expressed Rab1b-EGFP (to avoid nonspecific Rab1 antibody labeling) with GM130 or KDEL, markers of Golgi and ER, respectively.…”

Section: Sacsin Domains Alter Rab1b Subcellular Distribution and Asso...mentioning

confidence: 99%

Interactors of sacsin’s DNAJ domain identify function in organellar transport and membrane composition relevant to ARSACS pathogenesis

Paré,

Cheng-Boivin,

Dabbaghizadeh

et al. 2024

Preprint

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Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by loss of function mutations in theSACSgene encoding sacsin, a 520kDa protein with multiple functional domains. The goal of this study was to identify client proteins interacting with the J domain, a cochaperone domain interacting with Hsp70 chaperones, to gain insights into sacsin’s function and its disruption in experimental models of ARSACS. Pull downs from mouse brain identified Rabs and Rab-associated proteins including Rab1b, ARF5 and endophilin B2, involved in organelle trafficking. In cell and mouse models of ARSACS, higher molecular weight species of Rab1b were identified on SDS-PAGE in addition to the normal 25kDa band and Rab1was retained in the soma along with membranous organelles (i.e., ER, Golgi and ATG9 autophagic vesicles). These changes were reversed by expression of the DNAJ domain or the Ubl domain of sacsin and occurred independent of the formation of abnormal bundles of intermediate filaments, a key feature of ARSACS. Although Rab1b was associated with both Golgi and ER in bothSacs+/+andSacs-/-cells, expression of the DNAJ domain or the Ubl domain of sacsin increased Rab1b association with ER and restored normal electrophoretic mobility. Finally, subcellular distribution of another membrane protein, neuroplastin, a key receptor for synapse formation and plasticity, also was impaired, pointing to a general problem in Rab-dependent membrane trafficking in the absence of sacsin.

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“…Small GTPases were identified in proteomes of virion preparations (HCMV proteomes 1–5 and HSV-1 proteome 6), NVEPs (NV), l EVs (L), and s EVs (S) (proteome 7). The reported localization in membrane organelles of non-infected cells is shown by a color code to illustrate the preferred localization [ 49 , 59 , 60 , 69 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. Proteomes used for analysis and legends are described in Figure 3 .…”

Section: Figurementioning

confidence: 99%

Host Cell Signatures of the Envelopment Site within Beta-Herpes Virions

Lučin

Zagorac

Marcelić

et al. 2022

IJMS

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Beta-herpesvirus infection completely reorganizes the membrane system of the cell. This system is maintained by the spatiotemporal arrangement of more than 3000 cellular proteins that continuously adapt the configuration of membrane organelles according to cellular needs. Beta-herpesvirus infection establishes a new configuration known as the assembly compartment (AC). The AC membranes are loaded with virus-encoded proteins during the long replication cycle and used for the final envelopment of the newly formed capsids to form infectious virions. The identity of the envelopment membranes is still largely unknown. Electron microscopy and immunofluorescence studies suggest that the envelopment occurs as a membrane wrapping around the capsids, similar to the growth of phagophores, in the area of the AC with the membrane identities of early/recycling endosomes and the trans-Golgi network. During wrapping, host cell proteins that define the identity and shape of these membranes are captured along with the capsids and incorporated into the virions as host cell signatures. In this report, we reviewed the existing information on host cell signatures in human cytomegalovirus (HCMV) virions. We analyzed the published proteomes of the HCMV virion preparations that identified a large number of host cell proteins. Virion purification methods are not yet advanced enough to separate all of the components of the rich extracellular material, including the large amounts of non-vesicular extracellular particles (NVEPs). Therefore, we used the proteomic data from large and small extracellular vesicles (lEVs and sEVs) and NVEPs to filter out the host cell proteins identified in the viral proteomes. Using these filters, we were able to narrow down the analysis of the host cell signatures within the virions and determine that envelopment likely occurs at the membranes derived from the tubular recycling endosomes. Many of these signatures were also found at the autophagosomes, suggesting that the CMV-infected cell forms membrane organelles with phagophore growth properties using early endosomal host cell machinery that coordinates endosomal recycling.

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

Cited by 11 publications

References 219 publications

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model

Interactors of sacsin’s DNAJ domain identify function in organellar transport and membrane composition relevant to ARSACS pathogenesis

Host Cell Signatures of the Envelopment Site within Beta-Herpes Virions

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