Involvement of Mitochondria in Parkinson’s Disease DOI Open Access
Chi‐Jing Choong, Hideki Mochizuki

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 17027 - 17027

Published: Dec. 1, 2023

Mitochondrial dysregulation, such as mitochondrial complex I deficiency, increased oxidative stress, perturbation of dynamics and mitophagy, has long been implicated in the pathogenesis PD. Initiating from observation that toxins cause PD-like symptoms DNA mutations are associated with risk PD, many mutated genes linked to familial forms including PRKN, PINK1, DJ-1 SNCA, have also found affect features. Recent research uncovered a much more involvement mitochondria Disruption quality control coupled abnormal secretion contents dispose damaged organelles may play role Furthermore, due its bacterial ancestry, circulating DNAs can function damage-associated molecular patterns eliciting inflammatory response. In this review, we summarize discuss connection between dysfunction highlighting triggers disease process, intra- extracellular roles PD well therapeutic potential transplantation.

Language: Английский

Mitochondrial dysfunction: mechanisms and advances in therapy DOI Creative Commons

Zong Yao,

Hao Li, Peng Liao

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 15, 2024

Abstract Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation disease progression. Particularly, mitochondrial dysfunctions identified many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, cancer. However, the multifaceted nature elusive phenotypic threshold dysfunction complicate our understanding contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among most important therapeutic targets. In recent years, strategies targeting have continuously emerged transitioned clinical trials. Advanced intervention such as using healthy replenish or replace damaged mitochondria, has shown promise preclinical trials various Mitochondrial components, mtDNA, mitochondria-located microRNA, associated proteins can be potential agents augment function immunometabolic diseases tissue injuries. Here, we review current knowledge pathophysiology concrete examples We also summarize treat perspective dietary supplements targeted therapies, well translational situation related pharmacology agents. Finally, this discusses innovations applications transplantation an advanced promising treatment.

Language: Английский

Citations

239
Alpha Synuclein: Neurodegeneration and Inflammation DOI Open Access
Gianluigi Forloni

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5914 - 5914

Published: March 21, 2023

Alpha-Synuclein (α-Syn) is one of the most important molecules involved in pathogenesis Parkinson’s disease and related disorders, synucleinopathies, but also several other neurodegenerative disorders with a more elusive role. This review analyzes activities α-Syn, different conformational states, monomeric, oligomeric fibrils, relation to neuronal dysfunction. The damage induced by α-Syn various conformers will be analyzed its capacity spread intracellular aggregation seeds prion-like mechanism. In view prominent role inflammation virtually all activity illustrated considering influence on glial reactivity. We others have described interaction between general cerebral dysfunctional α-Syn. Differences microglia astrocyte activation been observed when vivo presence oligomers has combined lasting peripheral inflammatory effect. reactivity was amplified, while astrocytes were damaged double stimulus, opening new perspectives for control synucleinopathies. Starting from our studies experimental models, we extended perspective find useful pointers orient future research potential therapeutic strategies disorders.

Language: Английский

Citations

59
Axonal energy metabolism, and the effects in aging and neurodegenerative diseases DOI Creative Commons
Sen Yang, Jung Hyun Park, Hui‐Chen Lu

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: July 20, 2023

Abstract Human studies consistently identify bioenergetic maladaptations in brains upon aging and neurodegenerative disorders of (NDAs), such as Alzheimer’s disease, Parkinson’s Huntington’s Amyotrophic lateral sclerosis. Glucose is the major brain fuel glucose hypometabolism has been observed regions vulnerable to NDAs. Many susceptible are topological central hub connectome, linked by densely interconnected long-range axons. Axons, key components have high metabolic needs support neurotransmission other essential activities. Long-range axons particularly injury, neurotoxin exposure, protein stress, lysosomal dysfunction, etc. Axonopathy often an early sign neurodegeneration. Recent ascribe axonal maintenance failures local dysregulation. With this review, we aim stimulate research exploring metabolically oriented neuroprotection strategies enhance or normalize bioenergetics NDA models. Here start summarizing evidence from human patients animal models reveal correlation between connectomic disintegration aging/NDAs. To encourage mechanistic investigations on how dysregulation occurs during aging/NDAs, first review current literature distinct subdomains: axon initial segments, myelinated arbors harboring pre-synaptic boutons. In each subdomain, focus organization, activity-dependent regulation system, external glial support. Second, mechanisms regulating nicotinamide adenine dinucleotide (NAD + ) homeostasis, molecule for energy metabolism processes, including NAD biosynthetic, recycling, consuming pathways. Third, highlight innate vulnerability connectome discuss its perturbation As deficits developing into NDAs, especially asymptomatic phase, they likely exaggerated further impaired energetic cost neural network hyperactivity, pathology. Future interrogating causal relationship vulnerability, axonopathy, amyloid/tau pathology, cognitive decline will provide fundamental knowledge therapeutic interventions.

Language: Английский

Citations

49
Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control DOI

Xingyu Long,

Min Liu,

Yayun Nan

et al.

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(18)

Published: Jan. 15, 2024

Abstract Mitochondria, widely known as the energy factories of eukaryotic cells, have a myriad vital functions across diverse cellular processes. Dysfunctions within mitochondria serve catalysts for various diseases, prompting widespread demise. Mounting research on remedying damaged indicates that constitute valuable target therapeutic intervention against diseases. But less clinical practice and lower recovery rate imply limitation traditional drugs, which need further breakthrough. Nanotechnology has approached favorable regiospecific biodistribution high efficacy by capitalizing excellent nanomaterials targeting drug delivery. Mitochondria‐remedying nanodrugs achieved ideal effects. This review elucidates significance in cells organs, while also compiling mortality data related Correspondingly, nanodrug‐mediate strategies applicable mitochondria‐remedying disease are detailed, with full understanding roles dysfunction advantages nanodrugs. In addition, future challenges directions discussed. conclusion, this provides comprehensive insights into design development nanodrugs, aiming to help scientists who desire extend their fields engage interdisciplinary subject.

Language: Английский

Citations

30
Key genes and convergent pathogenic mechanisms in Parkinson disease DOI
Robert Coukos, Dimitri Krainc

Nature reviews. Neuroscience, Journal Year: 2024, Volume and Issue: 25(6), P. 393 - 413

Published: April 10, 2024

Language: Английский

Citations

28
Cell biology of Parkinson's disease: Mechanisms of synaptic, lysosomal, and mitochondrial dysfunction DOI
Sarah M. Brooker, G Naylor, Dimitri Krainc

et al.

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 85, P. 102841 - 102841

Published: Feb. 1, 2024

Language: Английский

Citations

26
Discovery of potent inhibitors of α-synuclein aggregation using structure-based iterative learning DOI Creative Commons
Robert I. Horne, Ewa A. Andrzejewska, Parvez Alam

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(5), P. 634 - 645

Published: April 17, 2024

Abstract Machine learning methods hold the promise to reduce costs and failure rates of conventional drug discovery pipelines. This issue is especially pressing for neurodegenerative diseases, where development disease-modifying drugs has been particularly challenging. To address this problem, we describe here a machine approach identify small molecule inhibitors α-synuclein aggregation, process implicated in Parkinson’s disease other synucleinopathies. Because proliferation aggregates takes place through autocatalytic secondary nucleation, aim compounds that bind catalytic sites on surface aggregates. achieve goal, use structure-based an iterative manner first then progressively optimize nucleation inhibitors. Our results demonstrate leads facile identification two orders magnitude more potent than previously reported ones.

Language: Английский

Citations

17
Pathogenesis of Parkinson’s Disease DOI
Bin Xiao, Zhidong Zhou, Yinxia Chao

et al.

Neurologic Clinics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

2
Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism DOI Creative Commons

Pascale Baden,

María José Pérez, Hariam Raji

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 6, 2023

Abstract Mutations in GBA1 , the gene encoding lysosomal enzyme β-glucocerebrosidase (GCase), which cause Gaucher’s disease, are most frequent genetic risk factor for Parkinson’s disease (PD). Here, we employ global proteomic and single-cell genomic approaches stable cell lines as well induced pluripotent stem (iPSC)-derived neurons midbrain organoids to dissect mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from cytosol into mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, promotes maintenance complex I (CI) integrity function. Furthermore, interacts with quality control proteins HSP60 LONP1. Disease-associated mutations impair CI stability function enhance interaction machinery. These findings reveal a role suggest defective activity energy metabolism may drive pathogenesis GCase-linked

Language: Английский

Citations

36
Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson’s disease mouse model DOI Creative Commons
Tracy-Shi Zhang Fang, Yu Sun, Andrew C. Pearce

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 13, 2023

Abstract Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson’s disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN PINK1, mutated autosomal recessive PD, regulate preferential autophagic clearance dysfunctional mitochondria (“mitophagy”) by inducing ubiquitylation proteins, process counteracted deubiquitylation via USP30. Here we show that loss USP30 Usp30 knockout mice protects against behavioral deficits increased mitophagy, decreased phospho-S129 αSyn, attenuation SN neuronal induced αSyn. These observations were recapitulated with potent, selective, brain-penetrant inhibitor, MTX115325, good drug-like properties. data strongly support further study inhibition as potential disease-modifying therapy for

Language: Английский

Citations

36