Hallmarks of neurodegenerative diseases

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Язык: Английский

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Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

Frontiers in Molecular Neuroscience, Год журнала: 2019, Номер 12

Опубликована: Фев. 14, 2019

TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits as inclusion bodies the brain spinal cord of patients with motor neuron diseases: amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD). While majority ALS cases (90-95%) are sporadic (sALS), among familial 5-10% involve inheritance mutations TARDBP gene remaining due to other genes such as: C9ORF72, SOD1, FUS, NEK1 etc. Strikingly however, (up 97%) also contain deposited neuronal inclusions, which suggests its pivotal role pathology. Thus, unravelling molecular mechanisms pathology, seems central therapeutics, hence, we comprehensively review current understanding TDP-43's pathology ALS. We discuss roles mutations, cytoplasmic mis-localization aberrant post-translational modifications Also, evaluate amyloid-like vitro aggregation, physiological versus pathological oligomerization vivo, liquid-liquid phase separation (LLPS), potential prion-like propagation propensity inclusions. Finally, describe various evolving TDP-43-induced toxicity impairment endocytosis mitotoxicity emerging strategies towards disaggregation therapeutics.

Язык: Английский

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Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

Developmental Cell, Год журнала: 2020, Номер 55(1), С. 45 - 68

Опубликована: Окт. 1, 2020

Язык: Английский

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A Liquid to Solid Phase Transition Underlying Pathological Huntingtin Exon1 Aggregation

Molecular Cell, Год журнала: 2018, Номер 70(4), С. 588 - 601.e6

Опубликована: Май 1, 2018

Huntington's disease is caused by an abnormally long polyglutamine tract in the huntingtin protein. This leads to generation and deposition of N-terminal exon1 fragments protein intracellular aggregates. We combined electron tomography quantitative fluorescence microscopy analyze structural material properties assemblies mammalian cells, yeast, vitro. found that proteins can form reversible liquid-like assemblies, a process driven huntingtin's polyQ proline-rich region. In cells vitro, converted solid-like with fibrillar structure. Intracellular phase transitions could play role initiating irreversible pathological aggregation.

Язык: Английский

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Innate Immunity and Neurodegeneration

Annual Review of Medicine, Год журнала: 2017, Номер 69(1), С. 437 - 449

Опубликована: Ноя. 6, 2017

The innate immune system plays diverse roles in health and disease. It represents the first line of defense against infection is involved tissue repair, wound healing, clearance apoptotic cells cellular debris. Excessive or nonresolving activation can lead to systemic local inflammatory complications cause contribute development diseases. In brain, microglia represent key cells, which are brain development, maturation, homeostasis. Impaired microglial function, either through aberrant decreased functionality, occur during aging neurodegeneration, resulting inflammation thought neurodegenerative This review highlights recent advances our understanding influence immunity on disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's Huntington's

Язык: Английский

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Genetics and Pathogenesis of Parkinson's Syndrome

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2022, Номер 18(1), С. 95 - 121

Опубликована: Сен. 13, 2022

Parkinson's disease (PD) is clinically, pathologically, and genetically heterogeneous, resisting distillation to a single, cohesive disorder. Instead, each affected individual develops virtually unique form of syndrome. Clinical manifestations consist variable motor nonmotor features, myriad overlaps are recognized with other neurodegenerative conditions. Although most commonly characterized by alpha-synuclein protein pathology throughout the central peripheral nervous systems, distribution varies pathologies modify PD or trigger similar manifestations. Nearly all influenced. More than 100 genes genetic loci have been identified, cases likely arise from interactions among many common rare variants. Despite its complex architecture, insights experimental dissection coalesce reveal unifying biological themes, including synaptic, lysosomal, mitochondrial, andimmune-mediated mechanisms pathogenesis. This emerging understanding syndrome, coupled advances in biomarkers targeted therapies, presages successful precision medicine strategies.

Язык: Английский

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Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(7), С. 2431 - 2431

Опубликована: Март 31, 2020

Alzheimer’s disease (AD) and Parkinson’s (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A clinical course is proteinopathy-induced neural dysfunction leading anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology symptomatology little value for sake prevention drug development. Overviewing pathomechanism NDs, this review incorporates systematic reviews inflammatory cytokines tryptophan metabolites kynurenines (KYNs) human samples, present an inferential method explore potential links behind NDs. The results revealed increases pro-inflammatory neurotoxic KYNs in anti-inflammatory AD, PD, Huntington’s (HD), Creutzfeldt–Jakob disease, immunodeficiency virus (HIV)-associated neurocognitive disorders, decreases neuromodulatory HD. reinforced strong link between inflammation KYNs, confirmed activation adaptive immune response, suggested possible role decrease all which may contribute development chronic low grade inflammation. Commonalities multifactorial NDs were discussed limit criteria, need preclinical biomarkers, approach search initiation factors

Язык: Английский

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Impact of Natural Compounds on Neurodegenerative Disorders: From Preclinical to Pharmacotherapeutics

Journal of Clinical Medicine, Год журнала: 2020, Номер 9(4), С. 1061 - 1061

Опубликована: Апрель 8, 2020

Among the major neurodegenerative disorders (NDDs), Alzheimer’s disease (AD) and Parkinson’s (PD), are a huge socioeconomic burden. Over many centuries, people have sought cure for NDDs from natural herbals. Many medicinal plants their secondary metabolites reported with ability to alleviate symptoms of NDDs. The mechanisms identified, through which phytochemicals exert neuroprotective effects potential maintenance neurological health in ageing, include antioxidant, anti-inflammatory, antithrombotic, antiapoptotic, acetylcholinesterase monoamine oxidase inhibition neurotrophic activities. This article reviews action some herbal products treatment according molecular targets, as well regional sources (Asia, America Africa). A number studies demonstrated beneficial properties plant extracts or bioactive compounds against Herbal may potentially offer new options patients NDDs, is cheaper culturally suitable alternative conventional therapies millions world age-related

Язык: Английский

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A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology

Nature Neuroscience, Год журнала: 2018, Номер 22(1), С. 47 - 56

Опубликована: Дек. 5, 2018

Язык: Английский

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Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

Frontiers in Neuroscience, Год журнала: 2020, Номер 13

Опубликована: Янв. 29, 2020

Iron is an essential transition metal for numerous biologic processes in mammals. metabolism and homeostasis are regulated via several coordination mechanisms including absorption, utilization, recycling, storage.Iron dyshomeostasis can result intracellular excessive iron accumulation,thereby damaging cells, tissues organs through free oxygen radicals generation. Numerous studies have showed that overload of brain involved the pathological mechanism Alzheimer's disease.However,the underlying not been fully elucidated. Ferroptosis , a newly defined iron-dependent form cell death, which distinct from apoptosis, necrosis, autophagy other forms death,may provide us new viewpoints. Here, we summarizes current knowledge ferroptosis, reviews contributions ferroptosis disease.

Язык: Английский

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