Streamlined alpha-synuclein RT-QuIC assay for various biospecimens in Parkinson’s disease and dementia with Lewy bodies

Acta Neuropathologica Communications, Journal Year: 2021, Volume and Issue: 9(1)

Published: April 7, 2021

Definitive diagnosis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) relies on postmortem finding disease-associated alpha-synuclein (αSyn

Language: Английский

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Local molecular and global connectomic contributions to cross-disorder cortical abnormalities

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Aug. 10, 2022

Abstract Numerous brain disorders demonstrate structural abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these connectomic vulnerabilities remain unknown, has yet be studied in a single multi-disorder framework. Using MRI morphometry the ENIGMA consortium, we construct maps cortical abnormalities for thirteen neurodevelopmental, neurological, psychiatric N = 21,000 participants 26,000 controls, collected using harmonised processing protocol. We systematically compare multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, myelination (molecular vulnerability), as well global measures number connections, centrality, connection diversity (connectomic vulnerability). find relationship between vulnerability white-matter architecture that drives disorder profiles. Local attributes, particularly receptor profiles, constitute best predictors both disorder-specific morphology cross-disorder similarity. Finally, consistently subtended by small subset network epicentres bilateral sensory-motor, inferior temporal lobe, precuneus, superior parietal cortex. Collectively, our results highlight how local attributes connectivity jointly shape abnormalities.

Language: Английский

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Aquaporin-4 in glymphatic system, and its implication for central nervous system disorders

Neurobiology of Disease, Journal Year: 2023, Volume and Issue: 179, P. 106035 - 106035

Published: Feb. 15, 2023

The clearance function is essential for maintaining brain tissue homeostasis, and the glymphatic system main pathway removing interstitial solutes. Aquaporin-4 (AQP4) most abundantly expressed aquaporin in central nervous (CNS) an integral component of system. In recent years, many studies have shown that AQP4 affects morbidity recovery process CNS disorders through system, shows notable variability part pathogenesis these diseases. Therefore, there has been considerable interest as a potential promising target regulating improving neurological impairment. This review aims to summarize pathophysiological role plays several by affecting findings can contribute better understanding self-regulatory functions were involved provide new therapeutic alternatives incurable debilitating neurodegenerative future.

Language: Английский

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Common Mechanisms Underlying α-Synuclein-Induced Mitochondrial Dysfunction in Parkinson’s Disease

Journal of Molecular Biology, Journal Year: 2023, Volume and Issue: 435(12), P. 167992 - 167992

Published: Feb. 2, 2023

Language: Английский

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Imaging α-synuclein pathologies in animal models and patients with Parkinson’s and related diseases

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2540 - 2557.e8

Published: June 5, 2024

Deposition of α-synuclein fibrils is implicated in Parkinson's disease (PD) and dementia with Lewy bodies (DLB), while vivo detection pathologies these illnesses has been challenging. Here, we have developed a small-molecule ligand, C05-05, for visualizing deposits the brains living subjects. In optical positron emission tomography (PET) imaging mouse marmoset models demonstrated that C05-05 captured dynamic propagation fibrillogenesis along neural pathways, followed by disruptions structures. High-affinity binding 18F-C05-05 to aggregates human brain tissues was also proven vitro assays. Notably, PET-detectable signals were intensified midbrains PD DLB patients as compared healthy controls, providing first demonstration illnesses. Collectively, propose new technology offering neuropathology-based translational assessments allied disorders toward diagnostic therapeutic research development.

Language: Английский

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Brain clearance of protein aggregates: a close-up on astrocytes

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Jan. 16, 2024

Abstract Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation toxic intra- extracellular aggregates. Intracellular aggregates can enter space be subsequently transferred among different cell types, thus spreading between connected brain districts. Although microglia perform predominant role removal aggregated proteins, mounting evidence suggests that astrocytes actively contribute to clearing process. However, molecular mechanisms used by remove misfolded proteins are still largely unknown. Here we first provide brief overview progressive transition from soluble monomers insoluble fibrils characterizes amyloid referring α-Synuclein Tau as archetypical examples. We then highlight at basis astrocyte-mediated clearance with focus on their potential ability recognize, collect, internalize digest protein Finally, explore targeting future therapeutic approach for treatment disorders characterized accumulation.

Language: Английский

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Dysbiosis of the gut microbiota and its effect on α-synuclein and prion protein misfolding: consequences for neurodegeneration

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 16, 2024

Abnormal behavior of α-synuclein and prion proteins is the hallmark Parkinson’s disease (PD) illnesses, respectively, being complex neurological disorders. A primary cause protein aggregation, brain injury, cognitive loss in illnesses misfolding normal cellular (PrP C ) into an infectious form Sc ). Aggregation causes disruptions processes (PD), leading to dopamine-producing neurons motor symptoms. Alteration composition or activity gut microbes may weaken intestinal barrier make it possible for prions go from brain. The gut-brain axis linked neuroinflammation; metabolites produced by microbiota affect aggregation α-synuclein, regulate inflammation immunological responses, influence course neurotoxicity proteins, even if their targets are distinct proteins. This thorough analysis explores interactions that exist between neurodegenerative particularly involvement microbiota, a collection bacteria, archaea, fungi, viruses etc., various becoming increasingly recognized. microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, integrity through axis, which contributes development progression disease. review delves molecular mechanisms underlie these relationships, emphasizing effects microbial such as bacterial lipopolysaccharides (LPS), short-chain fatty acids (SCFAs) regulating functioning. Additionally, looks at how environmental dietary decisions whether they could be risk factors illnesses. study concludes highlighting critical role plays It also provides promising direction future research treatment approaches. People afflicted difficult ailments find hope new preventive therapeutic approaches diseases better understood.

Language: Английский

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In situ architecture of neuronal α-Synuclein inclusions

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: April 14, 2021

Abstract The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly fibrils, but recent reports pointed intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) image neuronal in situ at resolution. We show that seeded by aggregates produced recombinantly or purified from patient brain fibrils crisscrossing a variety cellular organelles. Using gold-labeled seeds, find aggregate seeding is predominantly mediated small which cytoplasmic grow unidirectionally. Detailed analysis membrane interactions revealed do not contact directly, and does drive clustering. Altogether, conclusively demonstrate intermixed with membranous organelles, illuminate mechanism interaction.

Language: Английский

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Innate and adaptive immune responses in Parkinson's disease

Progress in brain research, Journal Year: 2019, Volume and Issue: unknown, P. 169 - 216

Published: Dec. 5, 2019

Language: Английский

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Beyond the synucleinopathies: alpha synuclein as a driving force in neurodegenerative comorbidities

Translational Neurodegeneration, Journal Year: 2019, Volume and Issue: 8(1)

Published: Sept. 4, 2019

The fundamental role that alpha-synuclein (aSyn) plays in the pathogenesis of neurodegenerative synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, is a well-accepted fact. A wealth experimental evidence has linked this relatively small but ubiquitously expressed protein to plethora cytopathologic mechanisms suggests aSyn may be capable seeding progressive spread synucleinopathy throughout brain. Beyond abnormal deposition frequently seen variety other proteinopathies Alzheimer's disease. In spite fact frequency concomitant pathology these disorders such it can considered rule rather than exception, potential have received little attention. article we postulate key driving pathogenic processes comorbidities. addition reviewing proteinopathies, also consider our current understanding interaction disease-associated proteins, tau, TDP-43, amyloid-β prion protein, context neuropathologic studies describing anatomical sites pathology. We conclude growing body evidence, encompassing neuropathology human brain, animal models employing sophisticated methods probing protein-protein interaction, cumulatively suggest well positioned exert strong influence on hope stimulate research emerging field future exploring contribution comorbidities provide critical information pertaining diagnosis development vital disease modifying treatments for devastating diseases.

Language: Английский

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