Abstract
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.
Highlights
Due to the scarcity of effective treatments for neurodegenerative diseases, urgent searches for candidate cellular and molecular mechanisms to develop therapeutic interventions are underway [1,2,3,4,5,6,7,8]
In this review we focus the discussion on the abnormal activity of the Ras-related protein Rab5, the master regulatory guanosine triphosphatase (GTPase) in early endosomes and highlight its role as a mediator of Alzheimer’s disease (AD) and other neurodegenerative diseases
The main objectives of this review are as follows: (1) we briefly review the role of p38α in the cell, including the neuron; (2) we review the role of Rab5 in the cell and discuss the association of dysregulated Rab5 activity with neurodegenerative disease pathogenesis; (3) we discuss the connection between Rab5 and p38α; (4) we provide evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for brain-penetrant, selective p38α kinase inhibitors; and (5) we offer ideas for further investigations to increase the understanding of the mechanism of action of p38α kinase inhibitors on Rab5 in neurodegenerative disease
Summary
Due to the scarcity of effective treatments for neurodegenerative diseases, urgent searches for candidate cellular and molecular mechanisms to develop therapeutic interventions are underway [1,2,3,4,5,6,7,8]. It is becoming increasingly clear that different neurodegenerative diseases exhibit common, central processes associated with progressive neuronal dysfunction and death, revealing multifactorial pathologies, including proteotoxic stress, neuroinflammation, and other abnormalities [3,5,6,9,10]. Even though the species of accumulating proteins are distinct in different neurodegenerative diseases, increasing evidence indicates that defects in the protein clearance system play a central role in the gradual accumulation of protein aggregates. In this review we focus the discussion on the abnormal activity of the Ras-related protein Rab, the master regulatory guanosine triphosphatase (GTPase) in early endosomes and highlight its role as a mediator of AD and other neurodegenerative diseases. The main objectives of this review are as follows: (1) we briefly review the role of p38α in the cell, including the neuron; (2) we review the role of Rab in the cell and discuss the association of dysregulated Rab activity with neurodegenerative disease pathogenesis; (3) we discuss the connection between Rab and p38α; (4) we provide evidence that through modulating Rab activity there are therapeutic opportunities in neurodegenerative diseases for brain-penetrant, selective p38α kinase inhibitors; and (5) we offer ideas for further investigations to increase the understanding of the mechanism of action of p38α kinase inhibitors on Rab in neurodegenerative disease
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