Mitophagy in Alzheimer’s Disease and Other Age-Related Neurodegenerative Diseases

Cells, Год журнала: 2020, Номер 9(1), С. 150 - 150

Опубликована: Янв. 8, 2020

Mitochondrial dysfunction is a central aspect of aging and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis, Huntington’s disease. Mitochondria are the main cellular energy powerhouses, supplying most ATP by oxidative phosphorylation, which required to fuel essential neuronal functions. Efficient removal aged dysfunctional mitochondria through mitophagy, cargo-selective autophagy, crucial for mitochondrial maintenance health. Mechanistic studies into mitophagy have highlighted an integrated elaborate network that can regulate turnover. In this review, we provide updated overview recent discoveries advancements on pathways discuss molecular mechanisms underlying defects in disease other age-related as well therapeutic potential mitophagy-enhancing strategies combat these disorders.

Язык: Английский

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MicroRNAs in Alzheimer's disease: Potential diagnostic markers and therapeutic targets

Biomedicine & Pharmacotherapy, Год журнала: 2022, Номер 148, С. 112681 - 112681

Опубликована: Фев. 14, 2022

Alzheimer's disease (AD) is the most common neurodegenerative disease, with cognitive decline as primary clinical feature. According to epidemiological statistics, 50 million people worldwide are currently affected by disease. Although new drugs such aducanumab have been approved for use in treatment of AD, none them reversed progression AD. MicroRNAs (miRNAs) small molecule RNAs that exert their biological functions regulating expression intracellular proteins, and differential abundance varieties found between central peripheral tissues AD patients healthy controls. This article will summarise changes miRNAs process, potential role diagnostic markers therapeutic targets be explored.

Язык: Английский

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Oligodendrocytes enhance axonal energy metabolism by deacetylation of mitochondrial proteins through transcellular delivery of SIRT2

Neuron, Год журнала: 2021, Номер 109(21), С. 3456 - 3472.e8

Опубликована: Сен. 9, 2021

Язык: Английский

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Deregulated mitochondrial microRNAs in Alzheimer's disease: Focus on synapse and mitochondria

Ageing Research Reviews, Год журнала: 2021, Номер 73, С. 101529 - 101529

Опубликована: Ноя. 20, 2021

Язык: Английский

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Genetics of amyotrophic lateral sclerosis: seeking therapeutic targets in the era of gene therapy

Journal of Human Genetics, Год журнала: 2022, Номер 68(3), С. 131 - 152

Опубликована: Июнь 13, 2022

Abstract Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS motor neurons. success antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a neuron disease, has triggered paradigm shift developing therapies. causative genes and disease-modifying genes, including those sporadic ALS, have been identified one after another. Thus, the freedom target choice for gene expanded by ASO strategy, new avenues therapeutic development. Tofersen superoxide dismutase 1 (SOD1) was pioneer ALS. Improving protocols devising early interventions are vital. In this review, we updated knowledge We summarized genetic mutations familial their clinical features, focusing on SOD1 , fused sarcoma (FUS) transacting response DNA-binding protein. frequency C9ORF72 mutation low Japan, unlike Europe United States, while FUS more common, indicating vary ethnicity. A genome-wide association study revealed which could be novel therapy. current status prospects development were discussed, ethical issues. Furthermore, discussed potential axonal pathology as targets from perspective intervention, intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired transport, aberrant cytoskeleton, axon branching. simultaneously discuss important pathological states cell bodies: persistent stress granules, disrupted nucleocytoplasmic cryptic splicing. based elucidation intervention molecular expected become strategy

Язык: Английский

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Neuroprotection in glaucoma: Mechanisms beyond intraocular pressure lowering

Molecular Aspects of Medicine, Год журнала: 2023, Номер 92, С. 101193 - 101193

Опубликована: Июнь 16, 2023

Glaucoma is a common, complex, multifactorial neurodegenerative disease characterized by progressive dysfunction and then loss of retinal ganglion cells, the output neurons retina. most common cause irreversible blindness affects ∼80 million people worldwide with many more undiagnosed. The major risk factors for glaucoma are genetics, age, elevated intraocular pressure. Current strategies only target pressure management do not directly processes occurring at level cell. Despite to manage pressure, as 40% patients progress in least one eye during their lifetime. As such, neuroprotective that cell these great therapeutic need. This review will cover recent advances from basic biology on-going clinical trials neuroprotection covering degenerative mechanisms, metabolism, insulin signaling, mTOR, axon transport, apoptosis, autophagy, neuroinflammation. With an increased understanding both mechanisms disease, we closer than ever strategy glaucoma.

Язык: Английский

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Axonal energy metabolism, and the effects in aging and neurodegenerative diseases

Molecular Neurodegeneration, Год журнала: 2023, Номер 18(1)

Опубликована: Июль 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.

Язык: Английский

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Mechanisms and roles of mitochondrial localisation and dynamics in neuronal function

Neuronal Signaling, Год журнала: 2020, Номер 4(2)

Опубликована: Май 18, 2020

Neurons are highly polarised, complex and incredibly energy intensive cells, their demand for ATP during neuronal transmission is primarily met by oxidative phosphorylation mitochondria. Thus, maintaining the health efficient function of mitochondria vital integrity, viability synaptic activity. Mitochondria do not exist in isolation, but constantly undergo cycles fusion fission, actively transported around neuron to sites high demand. Intriguingly, axonal dendritic exhibit different morphologies. In axons small sparse whereas dendrites they larger more densely packed. The transport mechanisms mitochondrial dynamics that underlie these differences, functional implications, have been focus concerted investigation. Moreover, it now clear deficiencies can be a primary factor many neurodegenerative diseases. Here, we review role play function, how processes support dysfunction implicated disease.

Язык: Английский

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The role of mitophagy in the regulation of mitochondrial energetic status in neurons

Autophagy, Год журнала: 2021, Номер 17(12), С. 4182 - 4201

Опубликована: Март 24, 2021

Mitochondria are the main cellular energy powerhouses and supply most of in form ATP to fuel essential neuronal functions through oxidative phosphorylation (OXPHOS). In Alzheimer disease (AD), metabolic mitochondrial disruptions an early feature preceding any histopathological clinical manifestations. Mitochondrial malfunction is also linked synaptic defects AD. Mitophagy serves as a key quality control mechanism involving sequestration damaged mitochondria within autophagosomes their subsequent degradation lysosomes. However, it remains largely unknown whether mitophagy involved regulation metabolism neurons, if so, deficiency AD attributed dysfunction. Here we reveal that broadly activated metabolically enhanced neurons upon OXPHOS stimulation, which sustains high energetic activity by increasing turnover hence facilitating maintenance. Unexpectedly, AD-related mutant HsAPP Tg mouse brains, stimulation fails correct deficits but exacerbates synapse loss consequence failure. Excitingly, lysosomal enhancement restores impaired function promoting elimination mitochondria, protecting against damage brains. Taken together, propose new controls bioenergetic status furthering our understanding direct impact on AD-linked shedding light development novel therapeutic strategies treat combined with elevation proteolytic activity.Abbreviations: AD: disease; Aβ: amyloid-β; APP: amyloid beta precursor protein; AV: autophagic vacuole; CHX: cycloheximide; CYCS: cytochrome c, somatic; DIV: days vitro; FRET: Förster resonance transfer; Gln, glutamine; LAMP1: associated membrane protein 1; LE: late endosome; Mito: mitochondria; Δψm: potential; OCR: oxygen consumption rate; OXPHOS: phosphorylation; SQSTM1/p62: sequestosome RHEB: Ras homolog, mTORC1 binding; ROS: reactive species; STX1: syntaxin SYP: synaptophysin; Tg: transgenic; TMRE: tetramethylrhodamine ethyl ester; TEM: transmission electron microscopy; WT: wild type.

Язык: Английский

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Mitophagy regulates integrity of mitochondria at synapses and is critical for synaptic maintenance

EMBO Reports, Год журнала: 2020, Номер 21(9)

Опубликована: Июль 6, 2020

Язык: Английский

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