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.
Export Options
About this article
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 |
Call for Papers in Thematic Issues
Advancements in Proteomic and Peptidomic Approaches in Cancer Immunotherapy: Unveiling the Immune Microenvironment
The scope of this thematic issue centers on the integration of proteomic and peptidomic technologies into the field of cancer immunotherapy, with a particular emphasis on exploring the tumor immune microenvironment. This issue aims to gather contributions that illustrate the application of these advanced methodologies in unveiling the complex interplay ...read more
Artificial Intelligence for Protein Research
Protein research, essential for understanding biological processes and creating therapeutics, faces challenges due to the intricate nature of protein structures and functions. Traditional methods are limited in exploring the vast protein sequence space efficiently. Artificial intelligence (AI) and machine learning (ML) offer promising solutions by improving predictions and speeding up ...read more
Nutrition and Metabolism in Musculoskeletal Diseases
The musculoskeletal system consists mainly of cartilage, bone, muscles, tendons, connective tissue and ligaments. Balanced metabolism is of vital importance for the homeostasis of the musculoskeletal system. A series of musculoskeletal diseases (for example, sarcopenia, osteoporosis) are resulted from the dysregulated metabolism of the musculoskeletal system. Furthermore, metabolic diseases (such ...read more
Protein Folding, Aggregation and Liquid-Liquid Phase Separation
Protein folding, misfolding and aggregation remain one of the main problems of interdisciplinary science not only because many questions are still open, but also because they are important from the point of view of practical application. Protein aggregation and formation of fibrillar structures, for example, is a hallmark of a ...read more
Related Journals
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
The Therapeutic Potential of RNA Interference: Novel Approaches for Cancer Treatment
Current Pharmaceutical Biotechnology Inhibition of Disulfide Reductases as a Therapeutic Strategy
Current Enzyme Inhibition Role of Dietary Antioxidants in Neurodegenerative Diseases: Where are We Standing?
Current Pharmaceutical Design Regional Grey Matter Loss and Brain Disconnection Across Alzheimer Disease Evolution
Current Medicinal Chemistry Ethanolamine: A Potential Promoiety with Additional Effects on the Brain
CNS & Neurological Disorders - Drug Targets Recombinant Human Insulin-Like Growth Factor-1: A New Cardiovascular Disease Treatment Option?
Cardiovascular & Hematological Agents in Medicinal Chemistry Comparative Evaluation of Ethanolic Extracts of Bacopa monnieri, Evolvulus alsinoides, Tinospora cordifolia and their Combinations on Cognitive Functions in Rats
Current Aging Science Sweet and Sour - Oxidative and Carbonyl Stress in Neurological Disorders
CNS & Neurological Disorders - Drug Targets Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease
Current Alzheimer Research Systematic Evaluation of Drug-Loaded Hydrogels for Application in Osteosarcoma Treatment
Current Pharmaceutical Biotechnology Molecular Mechanisms of Inflammation. Anti-Inflammatory Benefits of Virgin Olive Oil and the Phenolic Compound Oleocanthal
Current Pharmaceutical Design Influence of Essential Trace Minerals and Micronutrient Insufficiencies on Harmful Metal Overload in a Mongolian Patient with Multiple Sclerosis
Current Aging Science New Pharmacological Approaches to the Cholinergic System: An Overview on Muscarinic Receptor Ligands and Cholinesterase Inhibitors
Recent Patents on CNS Drug Discovery (Discontinued) The Role of Mitochondria in Brain Aging and the Effects of Melatonin
Current Neuropharmacology Non-Ceruloplasmin Copper Distinguishes A Distinct Subtype of Alzheimer’s Disease: A Study of EEG-Derived Brain Activity
Current Alzheimer Research Volumetric Analysis of the Hypothalamus, Amygdala and Hippocampus in Non-Suicidal and Suicidal Mood Disorder Patients – A Post-Mortem Study
CNS & Neurological Disorders - Drug Targets Metals and Parkinson's Disease: Mechanisms and Biochemical Processes
Current Medicinal Chemistry The Emerging Role of the Cannabinoid Receptor Family in Peripheral and Neuro-immune Interactions
Current Drug Targets Mitochondrial Physiology and Toxicity (Mitotoxicity); Importance for the Immune System, Programmed Cell Death and Cancer
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Chronic Cerebrospinal Venous Insufficiency (CCSVI) and Multiple Sclerosis (MS): A Critical Review
CNS & Neurological Disorders - Drug Targets