New hopes for disease modification in Parkinson's Disease DOI Creative Commons
Werner Poewe, Klaus Seppi,

Kathrin Marini

et al.

Neuropharmacology, Journal Year: 2020, Volume and Issue: 171, P. 108085 - 108085

Published: April 13, 2020

To date, despite numerous clinical trials, no intervention has been demonstrated to modify the progression of Parkinson's disease (PD). However, over past decades encouraging progress made towards a better understanding molecular pathways relevant for neurodegenerative process in PD. This is also based on new insights into genetic architecture disease, revealing multiple novel targets potentially disease-modifying interventions. Important achievements have field risk markers and combinations thereof, form algorithms, will hopefully soon provide possibility identify affected individuals at yet prediagnostic or prodromal stages illness. Such phases would an ideal window neuroprotection trials. Taken together, these developments offer hope that breakthrough modifying course PD might be reached. In this article we summarize various approaches currently pursued quest. part special issue entitled 'The Quest Disease-Modifying Therapies Neurodegenerative Disorders'.

Language: Английский

Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers DOI Creative Commons
Lorenzo Barba, Federico Paolini Paoletti, G. Bellomo

et al.

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(4), P. 669 - 683

Published: Feb. 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

Language: Английский

Citations

57
Exploring the Role of Ubiquitin–Proteasome System in Parkinson's Disease DOI
Tapan Behl, Sachin Kumar, Ziyad M. Althafar

et al.

Molecular Neurobiology, Journal Year: 2022, Volume and Issue: 59(7), P. 4257 - 4273

Published: May 3, 2022

Language: Английский

Citations

40
Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models DOI Creative Commons
Susy Prieto Huarcaya, Alice Drobny, André R. A. Marques

et al.

Autophagy, Journal Year: 2022, Volume and Issue: 18(5), P. 1127 - 1151

Published: March 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.

Language: Английский

Citations

39
Clinical and diagnostic implications of Alzheimer’s disease copathology in Lewy body disease DOI
Lorenzo Barba, Samir Abu‐Rumeileh, Henryk Barthel

et al.

Brain, Journal Year: 2024, Volume and Issue: 147(10), P. 3325 - 3343

Published: July 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.

Language: Английский

Citations

10
Current trends in basic research on Parkinson’s disease: from mitochondria, lysosome to α-synuclein DOI Creative Commons
Hideaki Matsui, Ryōsuke Takahashi

Journal of Neural Transmission, Journal Year: 2024, Volume and Issue: 131(6), P. 663 - 674

Published: April 13, 2024

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra and other brain regions. A key pathological feature PD abnormal accumulation α-synuclein protein within affected neurons, manifesting as Lewy bodies neurites. Despite extensive research efforts spanning several decades, underlying mechanisms disease-modifying therapies remain elusive. This review provides an overview current trends basic on PD. Initially, it discusses involvement mitochondrial dysfunction pathogenesis PD, followed insights into role lysosomal disruptions vesicular transport system. Additionally, delves physiological roles α-synuclein, crucial associated with pathophysiology. Overall, purpose this to comprehend state elucidating intricate outline future directions understanding disease.

Language: Английский

Citations

9
The multi‐faceted role of mitochondria in the pathology of Parkinson’s disease DOI Open Access

Dennison Trinh,

Ahmad R. Israwi,

Lindsay R. Arathoon

et al.

Journal of Neurochemistry, Journal Year: 2020, Volume and Issue: 156(6), P. 715 - 752

Published: Aug. 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

Language: Английский

Citations

61
Overexpression of α‐synuclein inhibits mitochondrial Ca2+ trafficking between the endoplasmic reticulum and mitochondria through MAMs by altering the GRP75–IP3R interaction DOI
Adolfo Garcia Erustes, Manuela D’Eletto, Gabriel Cicolin Guarache

et al.

Journal of Neuroscience Research, Journal Year: 2021, Volume and Issue: 99(11), P. 2932 - 2947

Published: Sept. 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.

Language: Английский

Citations

48
Treadmill exercise reduces α-synuclein spreading via PPARα DOI Creative Commons
Debashis Dutta, Ramesh Kumar Paidi, Sumita Raha

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 40(2), P. 111058 - 111058

Published: July 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.

Language: Английский

Citations

32
α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis DOI Creative Commons
Pan Wang, Guoyu Lan, Bin Xu

et al.

Translational Neurodegeneration, Journal Year: 2023, Volume and Issue: 12(1)

Published: Aug. 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

Language: Английский

Citations

20
The small GTPase Rit2 modulates LRRK2 kinase activity, is required for lysosomal function and protects against alpha-synuclein neuropathology DOI Creative Commons
Julia Obergasteiger,

Anne-Marie Castonguay,

Sara Pizzi

et al.

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: March 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.

Language: Английский

Citations

18