Rab GTPases: Switching to Human Diseases

Guadagno, Noemi Antonella; Progida, Cinzia

doi:10.3390/cells8080909

Cited by 75 publications

(62 citation statements)

References 224 publications

(296 reference statements)

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“…Dysregulated Rab5 activity has been defined as a major pathogenic driver in AD [1,48,70]. Moreover, a pathogenic role of aberrant Rab5 is emerging in many of the same other neurodegenerative diseases that are being targeted by p38α inhibitor programs, including PD, DLB, ALS, and HD [71][72][73]. Rab5 is a member of a large family of Rab proteins involved with neuronal function [53,71] and a number of other Rab proteins have been connected to neurodegenerative disease.…”

Section: Role Of Dysregulated Rab5 In the Pathogenesis Of Neurodegenementioning

confidence: 99%

“…However, as will be discussed in Section 5, Rab5 activity has been robustly connected to p38 MAPK signaling, while no such connection has been established for the other Rab proteins. Therefore, this review is focused on Rab5, and the reader is referred to a number of other excellent recent reviews on the broader family of Rab proteins and their relation to the pathogenesis of neurodegenerative disease [71][72][73].…”

Section: Role Of Dysregulated Rab5 In the Pathogenesis Of Neurodegenementioning

confidence: 99%

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P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Germann¹,

Alam²

2020

IJMS

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Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

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Section: Role Of Dysregulated Rab5 In the Pathogenesis Of Neurodegenementioning

confidence: 99%

Section: Role Of Dysregulated Rab5 In the Pathogenesis Of Neurodegenementioning

confidence: 99%

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Germann¹,

Alam²

2020

IJMS

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“…Several previous studies provide experimental evidence to support a link between endosomal defects and neuronal pathology in NDs, which has been well-reviewed in recent articles (Kiral et al, 2018;Guadagno and Progida, 2019). For example, in postmortem brains of AD patients, enlargement of Rab5-positive EEs and upregulation of Rab4 were observed in pyramidal neurons of the prefrontal cortex at the early-stages (Cataldo et al, 2000), and upregulation of Rab4, Rab5, Rab7, and Rab27 was observed in the cholinergic basal forebrain neurons (Ginsberg et al, 2011).…”

Section: Evidence For the Involvement Of Local Rab-mediated Endocyticmentioning

confidence: 92%

Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

Chung

Park

et al. 2020

Front. Cell. Neurosci.

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Due to their enormous surface area compared to other cell types, neurons face unique challenges in properly handling supply and retrieval of the plasma membrane (PM)-a process termed PM turnover-in their distal areas. Because of the length and extensiveness of dendritic branches in neurons, the transport of materials needed for PM turnover from soma to distal dendrites will be inefficient and quite burdensome for somatic organelles. To meet local demands, PM turnover in dendrites most likely requires local cellular machinery, such as dendritic endocytic and secretory systems, dysregulation of which may result in dendritic pathology observed in various neurodegenerative diseases (NDs). Supporting this notion, a growing body of literature provides evidence to suggest the pathogenic contribution of dysregulated PM turnover to dendritic pathology in certain NDs. In this article, we present our perspective view that impaired dendritic endocytic and secretory systems may contribute to dendritic pathology by encumbering PM turnover in NDs.

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“…Rab proteins have been one of the families of the Ras superfamily mostly studied (Guadagno and Progida, 2019). However, their role in tumor progression emerged more recently.…”

Section: Rab Family Proteins and Their Role In Melanoma Metastasis Anmentioning

confidence: 99%

Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

Brito¹,

Barral

Pojo³

2020

Front. Cell Dev. Biol.

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The rising incidence and mortality rate associated with the metastatic ability of cutaneous melanoma represent a major public health concern. Cutaneous melanoma is one of the most invasive human cancers, but the molecular mechanisms are poorly understood. Moreover, currently available therapies are not efficient in avoiding melanoma lethality. In this context, new biomarkers of prognosis, metastasis, and response to therapy are necessary to better predict the disease outcome. Additionally, the knowledge about the molecular alterations and dysregulated pathways involved in melanoma metastasis may provide new therapeutic targets. Members of the Ras superfamily of small GTPases regulate various essential cellular activities, from signaling to membrane traffic and cytoskeleton dynamics. Therefore, it is not surprising that they are differentially expressed, and their functions subverted in several types of cancer, including melanoma. Indeed, Ras small GTPases were found to regulate melanoma progression and invasion. Hence, a better understanding of the mechanisms regulated by Ras small GTPases that are involved in melanoma tumorigenesis and progression may provide new therapeutic strategies to block these processes. Here, we review the current knowledge on the role of Ras small GTPases in melanoma aggressiveness and the molecular mechanisms involved. Furthermore, we summarize the known involvement of these proteins in melanoma metastasis and how these players influence the response to therapy.

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Rab GTPases: Switching to Human Diseases

Cited by 75 publications

References 224 publications

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

Dysregulated Plasma Membrane Turnover Underlying Dendritic Pathology in Neurodegenerative Diseases

Subversion of Ras Small GTPases in Cutaneous Melanoma Aggressiveness

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