Pathological structural conversion of α-synuclein at the mitochondria induces neuronal toxicity

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(9), P. 1134 - 1148

Published: Aug. 30, 2022

Abstract Aggregation of alpha-synuclein (α-Syn) drives Parkinson’s disease (PD), although the initial stages self-assembly and structural conversion have not been directly observed inside neurons. In this study, we tracked intracellular conformational states α-Syn using a single-molecule Förster resonance energy transfer (smFRET) biosensor, show here that converts from monomeric state into two distinct oligomeric in neurons concentration-dependent sequence-specific manner. Three-dimensional FRET-correlative light electron microscopy (FRET-CLEM) revealed seeding events occur preferentially on membrane surfaces, especially at mitochondrial membranes. The lipid cardiolipin triggers rapid oligomerization A53T α-Syn, is sequestered within aggregating lipid–protein complexes. Mitochondrial aggregates impair complex I activity increase reactive oxygen species (ROS) generation, which accelerates causes permeabilization membranes cell death. These processes were also induced pluripotent stem (iPSC)–derived harboring mutations patients with PD. Our study highlights mechanism de novo subsequent neuronal toxicity.

Language: Английский

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Optical tweezers-controlled hotspot for sensitive and reproducible surface-enhanced Raman spectroscopy characterization of native protein structures

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

Published: Feb. 26, 2021

Abstract Surface-enhanced Raman spectroscopy (SERS) has emerged as a powerful tool to detect biomolecules in aqueous environments. However, it is challenging identify protein structures at low concentrations, especially for the proteins existing an equilibrium mixture of various conformations. Here, we develop situ optical tweezers-coupled visualize and control hotspot between two Ag nanoparticle-coated silica beads, generating tunable reproducible SERS enhancements with single-molecule level sensitivity. This dynamic detection window placed microfluidic flow chamber passing-by proteins, which precisely characterizes three globular without perturbation their native states. Moreover, directly identifies structural features transient species alpha-synuclein among its predominant monomers physiological concentration 1 μM by reducing ensemble averaging. Hence, this platform holds promise resolve details dynamic, heterogeneous, complex biological systems.

Language: Английский

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Alpha-Synuclein Aggregation Pathway in Parkinson’s Disease: Current Status and Novel Therapeutic Approaches

Cells, Journal Year: 2022, Volume and Issue: 11(11), P. 1732 - 1732

Published: May 24, 2022

Following Alzheimer’s, Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, sharing an unclear pathophysiology, a multifactorial profile, and massive social costs worldwide. Despite this, no disease-modifying therapy available. PD tightly associated with α-synuclein (α-Syn) deposits, which become organised into insoluble, amyloid fibrils. As typical intrinsically disordered protein, α-Syn adopts monomeric, random coil conformation in aqueous solution, while its interaction lipid membranes drives transition of molecule part α-helical structure. The central unstructured region involved fibril formation by converting to well-defined, β-sheet rich secondary structures. Presently, most therapeutic strategies against are focused on designing small molecules, peptides, peptidomimetics that can directly target aggregation pathway. Other approaches include gene silencing, cell transplantation, stimulation intracellular clearance autophagy promoters, degradation pathways based immunotherapy In present review, we sum marise current advances related aggregation/neurotoxicity. These findings valuable arsenal for further development efficient, nontoxic, non-invasive protocols tackles onset progression future.

Language: Английский

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Mitochondrial dysfunction and neurological disorders: A narrative review and treatment overview

Life Sciences, Journal Year: 2023, Volume and Issue: 334, P. 122257 - 122257

Published: Nov. 8, 2023

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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Associations Between Diabetes Mellitus and Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(2), P. 542 - 542

Published: Jan. 10, 2025

Diabetes mellitus (DM) and neurodegenerative diseases/disturbances are worldwide health problems. The most common chronic conditions diagnosed in persons 60 years older type 2 diabetes (T2DM) cognitive impairment. It was found that is a major risk for decline, dementia, Parkinson's disease (PD), Alzheimer's (AD), Huntington's (HD), amyotrophic lateral sclerosis (ALS) other disorders. Different mechanisms of associations between these diseases have been suggested. For example, it postulated an impaired intracellular insulin signaling pathway, together with hyperglycemia hyperinsulinemia, may cause pathological changes, such as dysfunction the mitochondria, oxidative stress inflammatory responses, etc. association diseases, well associations, needs further investigation. aim this review to describe mellitus, especially 1 (T1DM) selected i.e., disease, sclerosis. Suggested also described.

Language: Английский

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Linking the Endoplasmic Reticulum to Parkinson’s Disease and Alpha-Synucleinopathy

Frontiers in Neuroscience, Journal Year: 2019, Volume and Issue: 13

Published: May 29, 2019

Accumulation of misfolded proteins is a central paradigm in neurodegeneration. Because the key role endoplasmic reticulum (ER) regulating protein homeostasis, last decade multiple reports implicated this organelle progression Parkinson's Disease (PD) and other neurodegenerative illnesses. In PD, dopaminergic neuron loss or more broadly neurodegeneration has been improved by overexpression genes involved ER stress response. addition, toxic alpha-synuclein (αS), main constituent proteinacious aggregates found tissue samples PD patients, shown to cause altering intracellular traffic, synaptic vesicles transport Ca2+ homeostasis. review, we will be summarizing evidence correlating impaired functionality pathogenesis, focusing our attention on how toxic, aggregated αS can promote cell death.

Language: Английский

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Fluid Biomarkers for Synaptic Dysfunction and Loss

Biomarker Insights, Journal Year: 2020, Volume and Issue: 15, P. 117727192095031 - 117727192095031

Published: Jan. 1, 2020

Synapses are the site for brain communication where information is transmitted between neurons and stored memory formation. Synaptic degeneration a global early pathogenic event in neurodegenerative disorders with reduced levels of pre- postsynaptic proteins being recognized as core feature Alzheimer’s disease (AD) pathophysiology. Together AD, other neurodevelopmental show altered synaptic homeostasis an important event, due to that, they commonly referred synaptopathies. The exact mechanisms synapse dysfunction different diseases not well understood their study would help understanding role degeneration, differences commonalities among them highlight candidate biomarkers specific disorders. assessment cerebrospinal fluid (CSF), which can reflect patients cognitive disorders, keen area interest. Substantial research efforts now directed toward investigation CSF pathology improve diagnosis at stage monitor clinical progression. In this review, we will first summarize pathological events that lead loss then discuss available data on established (eg, neurogranin, SNAP-25, synaptotagmin-1, GAP-43, α-syn) emerging vesicle glycoprotein 2A neuronal pentraxins) dysfunction, while highlighting possible utilities, specificity, technical challenges detection.

Language: Английский

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Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

Antioxidants, Journal Year: 2020, Volume and Issue: 9(10), P. 1007 - 1007

Published: Oct. 16, 2020

Currently, neurodegenerative diseases are a major cause of disability around the world. Parkinson’s disease (PD) is second-leading disorder after Alzheimer’s disease. In PD, continuous loss dopaminergic neurons in substantia nigra causes dopamine depletion striatum, promotes primary motor symptoms resting tremor, bradykinesia, muscle rigidity, and postural instability. The risk factors PD comprise environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular injury, aging, hereditary defects. pathologic features include impaired protein homeostasis, mitochondrial dysfunction, nitric oxide, neuroinflammation, but interaction these contributing to not fully understood. neurotoxin-induced models, neurotoxins, for instance, 6-hydroxydopamine (6-OHDA), 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-Methyl-4-phenylpyridinium (MPP+), paraquat, rotenone, permethrin mainly impair respiratory chain, activate microglia, generate reactive oxygen species induce autooxidation neuronal apoptosis. Since no current treatment can cure using suitable animal model evaluate symptoms’ efficacy identify therapeutic targets drugs still needed. Hence, present review focuses on latest scientific developments different models with their mechanisms pathogenesis evaluation methods symptoms.

Language: Английский

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PARK Genes Link Mitochondrial Dysfunction and Alpha-Synuclein Pathology in Sporadic Parkinson’s Disease

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: July 6, 2021

Parkinson’s disease (PD) is an age-related neurodegenerative disorder affecting millions of people worldwide. The characterized by the progressive loss dopaminergic neurons and spread Lewy pathology (α-synuclein aggregates) in brain but pathogenesis remains elusive. PD presents substantial clinical genetic variability. Although its complex etiology has hampered breakthrough targeting modification, recent tools advanced our approaches. As such, mitochondrial dysfunction been identified as a major pathogenic hub for both familial sporadic PD. In this review, we summarize effect mutations 11 PARK genes ( SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, PLA2G6, FBXO7, VPS35, CHCHD2 , VPS13C ) on function well their relevance formation pathology. Overall, these play key roles homeostatic control (biogenesis mitophagy) functions (e.g., energy production oxidative stress), which may crosstalk with autophagy pathway, induce proinflammatory immune responses, increase stress that facilitate aggregation α-synuclein. Thus, rectifying dysregulation represents promising therapeutic approach neuroprotection

Language: Английский

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