Targeting mitophagy in Parkinson's disease
| Autor: | Thomas Briston, Tamaki Hoshikawa, Emily H. Clark, Aurelio Vázquez de la Torre |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
DUBs deubiquitinases Mitochondrion Biochemistry Parkin Antiparkinson Agents NAD nicotinamide adenine dinucleotide DAT dopamine transporter Mitophagy GFP green fluorescent protein IMS intermembrane space Drug discovery DA dopaminergic Parkinson Disease HTS high-throughput screen mitochondria PTMs posttranslational modifications GBA glucocerebrosidase biomarker KR kinetin riboside IMM inner mitochondrial membrane ATP adenosine triphosphate Mitochondrial processing peptidase Ubiquitin-Protein Ligases ETC electron transport chain Reviews SNc substantia nigra pars compacta PINK1 Biology PET positron emission tomography UA Urolithin A drug discovery MDVs mitochondrially derived vesicles 03 medical and health sciences Humans MPP mitochondrial processing peptidase Molecular Biology PD Parkinson’s disease PBMCs peripheral blood mononuclear cells 030102 biochemistry & molecular biology Mechanism (biology) Cell Biology ADP adenosine diphosphate Biomarker (cell) mitophagy 030104 developmental biology AMP adenosine monophosphate Mutation Parkinson’s disease cGMP cyclic guanosine monophosphate SPECT single-photon emission computed tomography Protein Kinases MTS mitochondrial targeting sequence Neuroscience |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.rev120.014294 |
| Popis: | The genetics and pathophysiology of Parkinson's disease (PD) strongly implicate mitochondria in disease aetiology. Elegant studies over the last two decades have elucidated complex molecular signaling governing the identification and removal of dysfunctional mitochondria from the cell, a process of mitochondrial quality control known as mitophagy. Mitochondrial deficits and specifically reduced mitophagy are evident in both sporadic and familial PD. Mendelian genetics attributes loss-of-function mutations in key mitophagy regulators PINK1 and Parkin to early-onset PD. Pharmacologically enhancing mitophagy and accelerating the removal of damaged mitochondria are of interest for developing a disease-modifying PD therapeutic. However, despite significant understanding of both PINK1-Parkin-dependent and -independent mitochondrial quality control pathways, the therapeutic potential of targeting mitophagy remains to be fully explored. Here, we provide a summary of the genetic evidence supporting the role for mitophagy failure as a pathogenic mechanism in PD. We assess the tractability of mitophagy pathways and prospects for drug discovery and consider intervention points for mitophagy enhancement. We explore the numerous hit molecules beginning to emerge from high-content/high-throughput screening as well as the biochemical and phenotypic assays that enabled these screens. The chemical and biological properties of these reference compounds suggest many could be used to interrogate and perturb mitochondrial biology to validate promising drug targets. Finally, we address key considerations and challenges in achieving preclinical proof-of-concept, including in vivo mitophagy reporter methodologies and disease models, as well as patient stratification and biomarker development for mitochondrial forms of the disease. |
| Databáze: | OpenAIRE |
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