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Parkinson's disease and mitophagy: an emerging role for LRRK2

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptom...

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Autores principales: Singh, Francois, Ganley, Ian G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106497/
https://www.ncbi.nlm.nih.gov/pubmed/33769432
http://dx.doi.org/10.1042/BST20190236
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author Singh, Francois
Ganley, Ian G.
author_facet Singh, Francois
Ganley, Ian G.
author_sort Singh, Francois
collection PubMed
description Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2.
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spelling pubmed-81064972021-05-18 Parkinson's disease and mitophagy: an emerging role for LRRK2 Singh, Francois Ganley, Ian G. Biochem Soc Trans Review Articles Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects around 2% of individuals over 60 years old. It is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain, which is thought to account for the major clinical symptoms such as tremor, slowness of movement and muscle stiffness. Its aetiology is poorly understood as the physiological and molecular mechanisms leading to this neuronal loss are currently unclear. However, mitochondrial and lysosomal dysfunction seem to play a central role in this disease. In recent years, defective mitochondrial elimination through autophagy, termed mitophagy, has emerged as a potential contributing factor to disease pathology. PINK1 and Parkin, two proteins mutated in familial PD, were found to eliminate mitochondria under distinct mitochondrial depolarisation-induced stress. However, PINK1 and Parkin are not essential for all types of mitophagy and such pathways occur in most cell types and tissues in vivo, even in the absence of overt mitochondrial stress — so-called basal mitophagy. The most common mutation in PD, that of glycine at position 2019 to serine in the protein kinase LRRK2, results in increased activity and this was recently shown to disrupt basal mitophagy in vivo. Thus, different modalities of mitophagy are affected by distinct proteins implicated in PD, suggesting impaired mitophagy may be a common denominator for the disease. In this short review, we discuss the current knowledge about the link between PD pathogenic mutations and mitophagy, with a particular focus on LRRK2. Portland Press Ltd. 2021-04-30 2021-03-26 /pmc/articles/PMC8106497/ /pubmed/33769432 http://dx.doi.org/10.1042/BST20190236 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Review Articles
Singh, Francois
Ganley, Ian G.
Parkinson's disease and mitophagy: an emerging role for LRRK2
title Parkinson's disease and mitophagy: an emerging role for LRRK2
title_full Parkinson's disease and mitophagy: an emerging role for LRRK2
title_fullStr Parkinson's disease and mitophagy: an emerging role for LRRK2
title_full_unstemmed Parkinson's disease and mitophagy: an emerging role for LRRK2
title_short Parkinson's disease and mitophagy: an emerging role for LRRK2
title_sort parkinson's disease and mitophagy: an emerging role for lrrk2
topic Review Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106497/
https://www.ncbi.nlm.nih.gov/pubmed/33769432
http://dx.doi.org/10.1042/BST20190236
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