Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers

Movement Disorders, Год журнала: 2022, Номер 37(4), С. 669 - 683

Опубликована: Фев. 5, 2022

ABSTRACT The synuclein family includes three neuronal proteins, named α‐synuclein, β‐synuclein, and γ‐synuclein, that have peculiar structural features. α‐synuclein is largely known for being a key protein in the pathophysiology of Parkinson's disease (PD) other synucleinopathies, namely, dementia with Lewy bodies multisystem atrophy. role β‐synuclein γ‐synuclein less well understood terms physiological functions potential contribution to human diseases. has been investigated extensively both cerebrospinal fluid (CSF) blood as biomarker synucleinopathies. Recently, great attention also paid whose CSF levels seem reflect synaptic damage neurodegeneration independent presence synucleinopathy. In this review, we aim provide an overview on pathophysiological roles synucleins. Because poorly field synucleinopathy its are far from clear, focus interactions between PD. We discuss biomarkers improve diagnostic characterization thus highlighting their application clinical trials disease‐modifying therapies. © 2022 Authors. Movement Disorders published by Wiley Periodicals LLC behalf International Parkinson Disorder Society

Язык: Английский

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Exploring the Role of Ubiquitin–Proteasome System in Parkinson's Disease

Molecular Neurobiology, Год журнала: 2022, Номер 59(7), С. 4257 - 4273

Опубликована: Май 3, 2022

Язык: Английский

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Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

Autophagy, Год журнала: 2022, Номер 18(5), С. 1127 - 1151

Опубликована: Март 15, 2022

Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests involvement autophagy as well lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be major protease involved in degradation, its deficiency linked presence insoluble conformers brain mice and humans transcellular transmission aggregates. We here postulate that degradation can enhanced application recombinant human proform (rHsCTSD). Our results reveal rHsCTSD efficiently endocytosed neuronal cells, correctly targeted lysosomes matured an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) PD patients harboring A53T mutation within gene, we confirm reduction after treatment with rHsCTSD. Moreover, demonstrate decrease pathological primary ctsd-deficient mouse model dosing Boosting activity only clearance murine tissue, but also restored endo-lysosome function. findings indicate critical for Thus, enzyme replacement strategies utilizing may therapeutic interest other synucleinopathies aiming burden.Abbreviations: aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: ceroid lipofuscinosis; CNL10: lipofuscinosis type 10; Corr.: corrected; CTSD: cathepsin D; CTSB: B; DA: dopaminergic; DA-iPSn: cell-derived neurons; dox: doxycycline; ERT: therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c.: intracranially; IF: immunofluorescence; iPSC: cell; KO: knockout; LAMP1: associated membrane protein 1; LSDs: storage disorders; MAPT: microtubule tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form CTSD; neurofil.: neurofilament; PD: disease; proCTSD: PRNP: prion RFU: relative fluorescence units; rHsCTSD: proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus.

Язык: Английский

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Clinical and diagnostic implications of Alzheimer’s disease copathology in Lewy body disease

Brain, Год журнала: 2024, Номер 147(10), С. 3325 - 3343

Опубликована: Июль 11, 2024

Concomitant Alzheimer's disease (AD) pathology is a frequent event in the context of Lewy body (LBD), occurring approximately half all cases. Evidence shows that LBD patients with AD copathology show an accelerated course, greater risk cognitive decline and overall poorer prognosis. However, LBD-AD cases may heterogeneous motor non-motor phenotypes higher dementia and, consequently, be not rarely misdiagnosed. In this review, we summarize current understanding by discussing synergistic effects neuropathological changes their clinical relevance. Furthermore, provide extensive overview neuroimaging fluid biomarkers under assessment for use possible diagnostic prognostic values. can predicted vivo means CSF, MRI PET markers, whereas most promising technique to date identifying different biological tissues α-synuclein seed amplification assay. Pathological imaging CSF are associated likelihood but do always mirror severity as pure AD. Implementing blood-based might allow faster screening copathology, thus improving sensitivity LBD-AD. Finally, discuss literature on novel candidate being exploited investigate other aspects neurodegeneration, such neuroaxonal injury, glial activation synaptic dysfunction. The thorough characterization should taken into account when considering differential diagnoses syndromes, evaluation individual level, guide symptomatic disease-modifying therapies.

Язык: Английский

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Immune cell metabolic dysfunction in Parkinson’s disease

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Март 24, 2025

Abstract Parkinson’s disease (PD) is a multi-system disorder characterized histopathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta . While etiology PD remains multifactorial and complex, growing evidence suggests that cellular metabolic dysfunction critical driver neuronal death. Defects metabolism related to energy production, oxidative stress, organelle health, protein homeostasis have been reported both immune cells PD. We propose these factors act synergistically drive aberrant inflammation CNS periphery PD, contributing hostile inflammatory environment which renders certain subsets vulnerable degeneration. This review highlights overlap between established deficits with emerging findings central peripheral cells. By discussing rapidly expanding literature on immunometabolic we aim draw attention potential biomarkers facilitate future development immunomodulatory strategies prevent or delay progression

Язык: Английский

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The multi‐faceted role of mitochondria in the pathology of Parkinson’s disease

Journal of Neurochemistry, Год журнала: 2020, Номер 156(6), С. 715 - 752

Опубликована: Авг. 16, 2020

Abstract Mitochondria are essential for neuronal function. They produce ATP to meet energy demands, regulate homeostasis of ion levels such as calcium and reactive oxygen species that cause oxidative cellular stress. have also been shown protein synthesis within themselves, well the nucleus, influence synaptic plasticity. These roles especially important neurons, which higher demands greater susceptibility Dysfunction mitochondria has associated with several neurodegenerative diseases, including Parkinson's disease, Alzheimer's Huntington's Glaucoma Amyotrophic Lateral Sclerosis. The focus this review is on how why mitochondrial function linked pathology disease (PD). Many PD‐linked genetic mutations identified result in dysfunctional mitochondria, through a wide‐spread number mechanisms. In review, we describe susceptible neurons predisposed be vulnerable toxic events occur during process PD, central these pathways. We discuss ways proteins familial PD control function, both physiologically pathologically, along their implications genome‐wide association studies risk assessment. Finally, potential strategies modification enhancement. Ultimately, agents capable improving and/or restoring either alone, or conjunction other disease‐modifying may halt slow progression neurodegeneration disease. image

Язык: Английский

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Overexpression of α‐synuclein inhibits mitochondrial Ca²⁺ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75–IP3R interaction

Journal of Neuroscience Research, Год журнала: 2021, Номер 99(11), С. 2932 - 2947

Опубликована: Сен. 12, 2021

Mitochondria-associated ER membranes (MAMs) are formed by close and specific components in the contact sites between endoplasmic reticulum (ER) mitochondria, which participate several cell functions, including lipid metabolism, autophagy, Ca2+ signaling. Particularly, presence of α-synuclein (α-syn) MAMs was previously demonstrated, indicating a physical interaction among some proteins this region potential involvement dysfunctions. alterations associated with neurodegenerative diseases such as Parkinson's disease (PD) contribute to pathogenesis features. Here, we investigated effects α-syn on transfer from mitochondria WT- A30P α-syn-overexpressing SH-SY5Y or HEK293 cells. We observed that potentiates mitochondrial membrane (Δψm ) loss induced rotenone, increases mitophagy overload. Additionally, cells, found reduction ER-mitochondria through impairment GRP75-IP3R interaction, however, no alteration VDAC1-GRP75 interaction. Consequently, after release ER, cells demonstrated buffering suggesting deregulation MAM activity. Taken together, our data highlight importance α-syn/MAMs/Ca2+ axis potentially affects functions PD.

Язык: Английский

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Treadmill exercise reduces α-synuclein spreading via PPARα

Cell Reports, Год журнала: 2022, Номер 40(2), С. 111058 - 111058

Опубликована: Июль 1, 2022

This study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading A53T brain and protecting nigral dopaminergic neurons. Preformed α-syn fibril (PFF) seeding internal capsule young mice leads to increased substantia nigra motor cortex concomitant loss However, regular decreases protects neurons PFF-seeded mice. Accordingly, also mitigates α-synucleinopathy aged While investigating this mechanism, we have observed that induces activation peroxisome proliferator-activated receptor α (PPARα) stimulate lysosomal biogenesis via TFEB. remains unable TFEB reduce lacking PPARα, fenofibrate, a prototype PPARα agonist, reduces α-synucleinopathy. These results delineate beneficial function PPARα.

Язык: Английский

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α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis

Translational Neurodegeneration, Год журнала: 2023, Номер 12(1)

Опубликована: Авг. 25, 2023

The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only neurons but also glia, including astrocytes. mechanisms regulating astrocytic α-syn level aggregation remain unclear. More recently, it has been demonstrated that a part spreading occurs through extracellular vesicles (EVs), although unknown whether this process involved astrocytes PD. It known, however, EVs derived from the central nervous system exist blood are extensively explored as biomarkers for other neurodegenerative disorders.Primary were transfected with A53T plasmid or exposed to aggregates. astrocyte-derived (AEVs) was assessed by nanoparticle tracking analysis immunofluorescence. lysosomal function evaluated Cathepsin assays, immunofluorescence levels Lamp1 Lamp2, LysoTracker Red staining. Apogee assays optimized measure GLT-1+ AEVs clinical cohorts 106 PD, 47 multiple atrophy (MSA), 103 healthy control (HC) test potential plasma biomarker differentiate forms parkinsonism.The number significantly increased primary deposition. mechanism partially attributed dysfunction. α-syn-carrying higher patients than HC MSA. integrative model combining total aggregated exhibited efficient diagnostic power differentiating AUC 0.915, MSA 0.877.Pathological deposition could increase secretion EVs, possibly α-syn-induced α-syn-containing peripheral may be effective diagnosis differential

Язык: Английский

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The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology

npj Parkinson s Disease, Год журнала: 2023, Номер 9(1)

Опубликована: Март 27, 2023

In Parkinson's disease (PD) misfolded alpha-synuclein (aSyn) accumulates in the substantia nigra, where dopaminergic neurons are progressively lost. The mechanisms underlying aSyn pathology still unclear, but they hypothesized to involve autophagy-lysosome pathway (ALP). LRRK2 mutations a major cause of familial and sporadic PD, kinase activity has been shown be involved pS129-aSyn inclusion modulation. We observed selective downregulation novel PD risk factor RIT2 vitro vivo. Rit2 overexpression G2019S-LRRK2 cells rescued ALP abnormalities diminished inclusions. vivo, viral mediated operated neuroprotection against AAV-A53T-aSyn. Furthermore, prevented A53T-aSyn-dependent increase On other hand, reduction levels leads defects ALP, similar those induced by mutation. Our data indicate that is required for correct lysosome function, inhibits overactive ameliorate impairment, counteracts aggregation related deficits. Targeting could represent an effective strategy combat neuropathology idiopathic PD.

Язык: Английский

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