Abstract
Mutations in LRRK2 comprise the most common cause for familial Parkinson’s disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators.
Keywords: Autophagy, endocytosis, GTPase, kinase, LRRK2, Parkinson’s disease, Rab7, Rab7L1.
Current Protein & Peptide Science
Title:LRRK2 and Parkinson's Disease: From Lack of Structure to Gain of Function
Volume: 18 Issue: 7
Author(s): Marian Blanca Ramirez, Jesus Madero-Perez, Pilar Rivero-Rios, Mar Martinez-Salvador, Antonio J. Lara Ordonez, Belen Fernandez, Elena Fdez and Sabine Hilfiker*
Affiliation:
- Institute of Parasitology and Biomedicine ,Spain
Keywords: Autophagy, endocytosis, GTPase, kinase, LRRK2, Parkinson’s disease, Rab7, Rab7L1.
Abstract: Mutations in LRRK2 comprise the most common cause for familial Parkinson’s disease (PD), and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum. LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic under certain conditions. These findings have spurred great interest in drug development approaches, and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight the most common proposed cellular roles so as to gain a better understanding of the cell type-specific effects of LRRK2 modulators.
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Cite this article as:
Blanca Ramirez Marian, Madero-Perez Jesus, Rivero-Rios Pilar, Martinez-Salvador Mar, Lara Ordonez J. Antonio, Fernandez Belen, Fdez Elena and Hilfiker Sabine*, LRRK2 and Parkinson's Disease: From Lack of Structure to Gain of Function, Current Protein & Peptide Science 2017; 18 (7) . https://dx.doi.org/10.2174/1389203717666160311121748
DOI https://dx.doi.org/10.2174/1389203717666160311121748 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
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