Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature

Movement Disorders, Journal Year: 2017, Volume and Issue: 32(11), P. 1504 - 1523

Published: Nov. 1, 2017

ABSTRACT Clinical–pathological studies remain the gold‐standard for diagnosis of Parkinson's disease (PD). However, mounting data from genetic PD autopsies challenge based on Lewy body pathology. Most confirmed risks show heterogenous neuropathology, even within kindreds, which may or not include We review literature cases with molecularly parkinsonism and summarize main findings SNCA (n = 25), Parkin 20, 17 bi‐allelic 3 heterozygotes), PINK1 5, 1 4 DJ‐1 1), LRRK2 55), GBA ( n 10 Gaucher patients parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 8 patients, 2 PD), MPAN 2), FBXO7, RAB39B , ATXN2 (SCA2), as well 22q deletion syndrome 3). Findings heterozygous mutation carriers genes that are traditionally considered recessively inherited also discussed. L ewy bodies be present in syndromes clinically distinctive (eg, ‐related neurodegeneration) absent clinical ‐PD ‐PD). Therefore, authors can conclude presence specific to diagnosed absence Interventions reduce alpha‐synuclein load more justified than other forms PD. The number reported remains small, there limited genotype‐clinical‐pathological‐phenotype studies. larger series required. © 2017 International Parkinson Movement Disorder Society

Language: Английский

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A walk through tau therapeutic strategies

Acta Neuropathologica Communications, Journal Year: 2019, Volume and Issue: 7(1)

Published: Feb. 15, 2019

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease related human tauopathies. There is a growing body evidence indicating that pathological tau species can travel from cell to spread pathology through brain. Throughout last decade, physiological have become attractive targets for AD therapies. Several therapeutic approaches been proposed, including inhibition protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, aggregation, active passive immunotherapies, silencing by antisense oligonucleotides. New therapeutics, across board, demonstrated ability prevent reduce lesions improve either cognitive motor impairment in variety animal models developing neurofibrillary pathology. The most advanced strategy treatment tauopathies remains immunotherapy, which has already reached stage drug development. vaccines humanised antibodies target intracellular extracellular spaces. Some them recognise amino-terminus carboxy-terminus, while others display binding abilities proline-rich area microtubule domains. main foci existing trials are on disease, progressive supranuclear palsy non-fluent primary aphasia. therapy offers new hope many fatal brain disorders. First efficacy data will be available end this decade.

Language: Английский

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Dementia with Lewy bodies and Parkinson’s disease-dementia: current concepts and controversies

Journal of Neural Transmission, Journal Year: 2017, Volume and Issue: 125(4), P. 615 - 650

Published: Dec. 8, 2017

Language: Английский

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

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(7), P. 2431 - 2431

Published: March 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

Language: Английский

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Plasma biomarkers of astrocytic and neuronal dysfunction in early‐ and late‐onset Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2019, Volume and Issue: 16(4), P. 681 - 695

Published: Dec. 24, 2019

We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD LOAD).

Language: Английский

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Tauopathies: new perspectives and challenges

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: April 7, 2022

Abstract Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with range phenotypes that include cognitive/behavioral-disorders, movement disorders, language and non-specific amnestic symptoms in advanced age. Pathologically, be classified based on the predominant tau isoforms inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) blood-based biomarkers have potential to used as routine diagnostic strategy evaluation patients tauopathies. As strongly linked neuropathologically genetically protein abnormalities, there is growing interest pursuing tau-directed therapeutics for disorders. Here we synthesize emerging lessons from clinical, pathological, genetic, experimental studies toward unified concept these may accelerate therapeutics. Conclusions Since still untreatable diseases, efforts been made depict clinical pathological characteristics, identify biomarkers, elucidate underlying pathogenesis achieve early diagnosis develop disease-modifying therapies.

Language: Английский

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The Evolving Landscape of Exosomes in Neurodegenerative Diseases: Exosomes Characteristics and a Promising Role in Early Diagnosis

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(1), P. 440 - 440

Published: Jan. 4, 2021

Neurodegenerative diseases (ND) remains to be one of the biggest burdens on healthcare systems and serves as a leading cause disability death. Alzheimer’s disease (AD) is among most common such disorders, followed by Parkinson’s (PD). The basic molecular details initiation pathology are still under research. Only recently, role exosomes has been linked progression these neurodegenerative diseases. Exosomes small bilipid layer enclosed extracellular vesicles, which were once considered cellular waste functionless. These nano-vesicles 30–150 nm in diameter carry specific proteins, lipids, functional mRNAs, high amounts non-coding RNAs (miRNAs, lncRNAs, circRNAs). As content known vary per their originating recipient cells, vesicles can utilized diagnostic biomarker for early detection. Here we review exosomes, biogenesis, composition, We have also provided characterization through an array available techniques. Their updated discussed. Finally, shed light novel field salivary potential candidate diagnosis compared biomarkers with other blood/cerebrospinal fluid (CSF) based within neurological ailments.

Language: Английский

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Calcium Dyshomeostasis in Alzheimer’s Disease Pathogenesis

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(9), P. 4914 - 4914

Published: May 6, 2021

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder that characterized by amyloid β-protein deposition in senile plaques, neurofibrillary tangles consisting of abnormally phosphorylated tau protein, and neuronal loss leading to cognitive decline dementia. Despite extensive research, exact mechanisms underlying AD remain unknown effective treatment not available. Many hypotheses have been proposed explain pathophysiology; however, there general consensus abnormal aggregation β peptide (Aβ) initial event triggering a pathogenic cascade degenerating events cholinergic neurons. The dysregulation calcium homeostasis has studied considerably clarify neurodegeneration induced Aβ. Intracellular acts as second messenger plays key role regulation functions, such neural growth differentiation, action potential, synaptic plasticity. hypothesis posits activation amyloidogenic pathway affects Ca2+ responsible for learning memory. Aβ can disrupt signaling through several mechanisms, increasing influx from extracellular space activating its release intracellular stores. Here, we review different molecular receptors involved possible therapeutic strategies improving treatment.

Language: Английский

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Connectome-based modelling of neurodegenerative diseases: towards precision medicine and mechanistic insight

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(10), P. 620 - 639

Published: Aug. 24, 2023

Language: Английский

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Does modulation of tau hyperphosphorylation represent a reasonable therapeutic strategy for Alzheimer’s disease? From preclinical studies to the clinical trials

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 28(6), P. 2197 - 2214

Published: June 1, 2023

Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was first pathological post-translational modification tau described Alzheimer's disease (AD), highlighting role PKs The therapeutic potential kinase inhibitors (PKIs)) and phosphatase 2 A (PP2A) activators AD has recently been explored several preclinical clinical studies variable outcomes. Where a number demonstrate visible reduction levels phospho-tau transgenic tauopathy models, no neurofibrillary lesions is observed. Amongst few PKIs PP2A that progressed trials, failed on efficacy front, only still unconfirmed positive trends. This suggests robust data needed unequivocally evaluate their efficacy. To this end, we take systematic look at results activators, evidence they provide regarding utility approach targeting modifying therapy.

Language: Английский

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