Next Article in Journal
Targeting on Gut Microbiota-Derived Metabolite Trimethylamine to Protect Adult Male Rat Offspring against Hypertension Programmed by Combined Maternal High-Fructose Intake and Dioxin Exposure
Next Article in Special Issue
Involvement of p38 MAPK in Synaptic Function and Dysfunction
Previous Article in Journal
Targeting Hypoxia-Driven Metabolic Reprogramming to Constrain Tumor Progression and Metastasis
Previous Article in Special Issue
Is p38 MAPK Associated to Drugs of Abuse-Induced Abnormal Behaviors?
Open AccessReview

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

EIP Pharma, Inc., Boston, MA 02116, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(15), 5485; https://doi.org/10.3390/ijms21155485
Received: 2 July 2020 / Revised: 25 July 2020 / Accepted: 30 July 2020 / Published: 31 July 2020
(This article belongs to the Special Issue P38 Signaling Pathway)
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. View Full-Text
Keywords: p38 MAPK; p38α; Rab5; endosome; Alzheimer’s; Lewy Bodies; amyloid-β; tau; α-synuclein p38 MAPK; p38α; Rab5; endosome; Alzheimer’s; Lewy Bodies; amyloid-β; tau; α-synuclein
Show Figures

Figure 1

MDPI and ACS Style

Germann, U.A.; Alam, J.J. P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease. Int. J. Mol. Sci. 2020, 21, 5485.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop