Key genes and convergent pathogenic mechanisms in Parkinson disease

Nature reviews. Neuroscience, Год журнала: 2024, Номер 25(6), С. 393 - 413

Опубликована: Апрель 10, 2024

Язык: Английский

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Involvement of Mitochondria in Parkinson’s Disease

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(23), С. 17027 - 17027

Опубликована: Дек. 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.

Язык: Английский

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PARK15/FBXO7 is dispensable for PINK1/Parkin mitophagy in iNeurons and HeLa cell systems

EMBO Reports, Год журнала: 2023, Номер 24(8)

Опубликована: Июнь 19, 2023

The protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria via a feed-forward mechanism involving (Ub) phosphorylation (pUb), activation, ubiquitylation mitochondrial outer membrane proteins to support the recruitment mitophagy receptors. substrate receptor FBXO7/PARK15 is mutated in an early-onset parkinsonian-pyramidal syndrome. Previous studies have proposed role for FBXO7 promoting Parkin-dependent mitophagy. Here, we systematically examine involvement depolarization

Язык: Английский

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FBXO7/ntc and USP30 antagonistically set the ubiquitination threshold for basal mitophagy and provide a target for Pink1 phosphorylation in vivo

PLoS Biology, Год журнала: 2023, Номер 21(8), С. e3002244 - e3002244

Опубликована: Авг. 3, 2023

Functional analyses of genes linked to heritable forms Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown regulate mitochondrial homeostasis. We investigated extent which its Drosophila orthologue, ntc, share functional homology explored role mitophagy vivo. show that ntc mutants partially phenocopy Pink1 parkin overexpression supresses phenotypes. Furthermore, can modulate basal a Pink1- parkin-independent manner by promoting ubiquitination proteins, mechanism is opposed deubiquitinase USP30. This serves as substrate for Pink1-mediated phosphorylation triggers stress-induced mitophagy. propose FBXO7/ntc works equilibrium with USP30 provide checkpoint quality control conditions vivo presents new avenue therapeutic approaches.

Язык: Английский

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Inhibition of USP30 Promotes Mitophagy by Regulating Ubiquitination of MFN2 by Parkin to Attenuate Early Brain Injury After SAH

Translational Stroke Research, Год журнала: 2023, Номер unknown

Опубликована: Дек. 26, 2023

Abstract Subarachnoid hemorrhage (SAH) is a type of stroke with high disability and mortality rate. Apoptosis caused by massive damage to mitochondria in neuron cells inflammatory responses extracellular ATP lead poor outcomes. USP30 deubiquitinating enzyme that inhibits mitophagy, resulting failure remove damaged timely manner after SAH; nevertheless, the pathway through which mitophagy unknown. This study evaluated neuroprotective role possible molecular basis inhibiting attenuate SAH-induced EBI promoting neuronal mitophagy. We used an vitro model hemoglobin exposure vivo intravascular perforation. Increased expression was found SAH vitro, inhibition mice treated MF094 resulted significant improvement neurological injury response mediated good outcomes, suggesting effect inhibition. In cultured neurons, promoted ubiquitination modification mitochondrial fusion protein 2 (MFN2) E3 ubiquitin ligase (Parkin), separating from healthy network prompting causing early clearance intracellular mitochondria, reducing onset apoptosis. The environment meliorated, reversing conversion microglia pro-inflammatory phenotype injury. had no autophagy-promoting on structurally functionally sound did not inhibit normal production. findings suggest has clear mitochondria.

Язык: Английский

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Post-translational modification and mitochondrial function in Parkinson’s disease

Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Янв. 11, 2024

Parkinson's disease (PD) is the second most common neurodegenerative with currently no cure. Most PD cases are sporadic, and about 5-10% of present a monogenic inheritance pattern. Mutations in more than 20 genes associated genetic forms PD. Mitochondrial dysfunction considered prominent player pathogenesis. Post-translational modifications (PTMs) allow rapid switching protein functions therefore impact various cellular including those related to mitochondria. Among PD-associated genes,

Язык: Английский

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Study of an FBXO7 patient mutation reveals Fbxo7 and PI31 co‐regulate proteasomes and mitochondria

FEBS Journal, Год журнала: 2024, Номер 291(12), С. 2565 - 2589

Опубликована: Март 11, 2024

Mutations in FBXO7 have been discovered to be associated with an atypical parkinsonism. We report here a new homozygous missense mutation paediatric patient that causes L250P substitution the dimerisation domain of Fbxo7. This alteration selectively ablates Fbxo7‐PI31 interaction and significant reduction Fbxo7 PI31 levels cells. Consistent their association proteasomes, fibroblasts reduced proteasome activity subunits. also show interacts MiD49/51 fission adaptor proteins, unexpectedly, acts facilitate SCF ‐mediated ubiquitination MiD49. The reduces ligase‐mediated subset its known substrates. Although expression was cells, there no effect on mitochondrial network. However, cells function mitophagy, higher ROS are less viable under stress. Our study demonstrates regulate proteasomes mitochondria reveals for enhancing E3 ubiquitin ligase activity.

Язык: Английский

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Mechanisms Associated with Mitophagy and Ferroptosis in Cerebral Ischemia-reperfusion Injury

Journal of Integrative Neuroscience, Год журнала: 2025, Номер 24(3)

Опубликована: Март 18, 2025

Ischemic stroke (IS) constitutes a major threat to human health. Vascular recanalization by intravenous thrombolysis and mechanical remain the most significant effective methods for relief of ischemia. Key elements these treatments include achieving blood-vessel recanalization, restoring brain-tissue reperfusion, preserving ischemic penumbra. However, in therapeutic goals vascular secondary damage brain tissue from cerebral ischemia-reperfusion injury (CIRI) must also be addressed. Despite advancements understanding pathological processes associated with CIRI, interventions prevent its onset progression are still lacking. Recent research has indicated that mitophagy ferroptosis critical mechanisms development significantly contribute IS CIRI because common targets co-occurrence mechanisms. Therefore, exploring summarizing potential connections between during is crucial. In present review, we mainly focused on mitochondrial autophagy ferroptosis, their interaction, CIRI. We believe data show strong relationship interactive regulation. This information may underpin new approaches prevention treatment subsequent

Язык: Английский

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Furin inhibits HSCs activation and ameliorates liver fibrosis by regulating PTEN‐L/PINK1/parkin mediated mitophagy in mouse

FASEB BioAdvances, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Abstract Hepatic Stellate cells (HSCs) play an important role during liver fibrosis progression; more and evidence indicates that mitophagy greatly regulates HSCs activation. mainly depends on the classical PINK1/Parkin pathway, which can be strongly regulated by phosphatase PTEN‐long (PTEN‐L). PTEN‐L cleaved Furin leading to functional changes in tumor regulation process. However, impact of interaction between remains unclear. Therefore, this study aims explore activation its potential mechanisms. Our results revealed expression was obviously up‐regulated mice fibrogenesis. We also found primary inhibited treatment vitro. Besides, studies showed LX‐2 cell proliferation migration were treatment. Further mitochondrial membrane (MMP) significantly reduced treatment, knockdown caused similar effects. These demonstrated promoting but inhibition persistent Furthermore, we constructed a mouse model CCl4‐induced method forced alleviation mice. findings provide new clue for understanding fibrogenesis highlight therapeutic hepatic fibrosis.

Язык: Английский

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ARMC1 partitions between distinct complexes and assembles MIRO with MTFR to control mitochondrial distribution

Science Advances, Год журнала: 2025, Номер 11(15)

Опубликована: Апрель 9, 2025

Maintaining an optimal mitochondrial distribution is critical to ensure adequate supply of energy and metabolites support important cellular functions. How cells balance dynamic processes achieve homeostasis incompletely understood. Here, we show that ARMC1 partitioning between distinct protein complexes a key determinant distribution. In one complex, the trafficking adaptor MIRO recruits ARMC1, which mediates assembly fission regulator (MTFR). MTFR stability depends on MIRO-MTFR specifically antagonize retrograde movement. another DNAJC11 facilitates release from mitochondria. Disrupting fails rescue aberrant distributions clustered in perinuclear area observed with deletion, while disrupting interaction leads excessive mitochondrially localized defects. Thus, abundance impact require whose mito-cytoplasmic shuttling balanced by tunes steady-state distributions.

Язык: Английский

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