scholarly journals Rab2 is a potent new target for enhancing autophagy in the treatment of Parkinson’s disease

2020 ◽  
Author(s):  
Janka Szinyákovics ◽  
Eszter Kiss ◽  
Fanni Keresztes ◽  
Tibor Vellai ◽  
Tibor Kovács
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Drug Targets ◽  
Disease Model ◽  
Alpha Synuclein ◽  
Small Gtpase ◽  
Rab Proteins ◽  
Receptor Complexes ◽  
Complex Forms

AbstractMacroautophagy is a lysosomal-dependent degradational pathway of eukaryotic cells, during which toxic, unnecessary, and damaged intracellular components are broken down. Autophagic activity declines with age, and this change could contribute to the accumulation of intracellular damage at advanced ages, causing cells to lose their functionality and vitality. This could be particularly problematic in post-mitotic cells include neurons, the mass destruction of which leads to different neurodegenerative diseases.We aim to discover new regulation points where autophagy could be specifically activated, and test these potential drug targets in Drosophila neurodegenerative disease models. One possible way to activate autophagy is through the enhancement of autophagosome-lysosome fusion to become autolysosome. This fusion is regulated by HOPS (homotypic fusion and protein sorting) and SNARE (Snap receptor) complexes. The HOPS complex forms a bridge between lysosome and autophagosome with the assistance of small GTPase Rab (Ras-associated binding) proteins. Thus, Rab proteins are essential for autolysosome maturation, and among Rab proteins, Rab2 is required for the degradation of autophagic cargo.Our results revealed that GTP-locked (constitutively active) Rab2 (Rab2 CA) expression reduces the levels of the autophagic substrate p62/Ref2P in dopaminergic neurons, and improved the climbing ability of animals during aging. The expression of Rab2 CA also increased lifespan in a Parkinson’s disease model (human mutant alpha-synuclein [A53T] overexpressed animals). In these animals, Rab2 CA expression significantly increased autophagic degradation as compared to control. These results may reveal a new, more specific drug target for autophagic activation treating today’s incurable neurodegenerative diseases.

Screening herbal medicines for the recovery of alpha-synuclein-induced Parkinson’s disease model of yeast

2012 ◽  
Vol 8 (4) ◽  
pp. 343-348 ◽  
Author(s):  
Sung-Hwa Sohn ◽  
Moonsik Yoon ◽  
Jaeyoon Kim ◽  
Hei-Lim Choi ◽  
Minkyu Shin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Disease Model ◽  
Herbal Medicines ◽  
Alpha Synuclein

scholarly journals Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson’s Disease

2020 ◽  
Vol 21 (22) ◽  
pp. 8666
Author(s):  
Dominika Fricova ◽  
Jana Harsanyiova ◽  
Alzbeta Kralova Trancikova
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Clinical Symptoms ◽  
Neuronal Degeneration ◽  
Alpha Synuclein ◽  
Diagnostic Methods ◽  
Alternative Methods ◽  
Peripheral Tissues ◽  
Potential Biomarker

The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general.

scholarly journals A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

2021 ◽  
Author(s):  
Judit Oláh ◽  
Attila Lehotzky ◽  
Tibor Szénási ◽  
Judit Ovádi
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Cell Types ◽  
Alpha Synuclein ◽  
Economic Problem ◽  
Innovative Therapy ◽  
New Strategy ◽  
Conformational Plasticity ◽  
Unique Specificity

With the aging of the population, Parkinson’s disease poses a serious socio-economic problem; there is no effective therapy that can arrest/revert the progression of the disease. The hallmarks of Parkinson’s disease and other synucleinopathies are the disordered alpha-synuclein and TPPP/p25. These proteins have neomorphic moonlighting characteristics by displaying both physiological and pathological functions. Physiologically TPPP/p25 regulates the dynamics/stability of the microtubules and is crucial for oligodendrocyte differentiation; while alpha-synuclein is involved in neuronal plasticity modulation and synaptic vesicle pool maintenance. In healthy brain, alpha-synuclein and TPPP/p25 occur predominantly in neurons and oligodendrocytes, respectively; however, they are co-enriched and co-localized in both cell types in brain inclusions in the cases of Parkinson’s disease and multiple system atrophy, respectively. The pathomechanisms of these diseases are largely unknown; the fatal species are the small, soluble homo- and hetero-associations of alpha-synuclein. These proteins with their high conformational plasticity and chameleon feature are challenging drug targets. Nevertheless, the contact surface of TPPP/p25-alpha-synuclein assemblies has been validated as a specific drug target. This new strategy with innovative impact, namely targeting the interface of the TPPP/p25-alpha-synuclein complex, could contribute to the development of anti-Parkinson drugs with unique specificity.

scholarly journals Inhibition by Multifunctional Magnetic Nanoparticles Loaded with Alpha-Synuclein RNAi Plasmid in a Parkinson's Disease Model

Theranostics ◽  
2017 ◽  
Vol 7 (2) ◽  
pp. 344-356 ◽  
Author(s):  
Shuiqin Niu ◽  
Ling-Kun Zhang ◽  
Li Zhang ◽  
Siyi Zhuang ◽  
Xiuyu Zhan ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Magnetic Nanoparticles ◽  
Disease Model ◽  
Alpha Synuclein

scholarly journals Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson’s disease model

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chunni Zhu ◽  
Tina Bilousova ◽  
Samantha Focht ◽  
Michael Jun ◽  
Chris Jean Elias ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Motor Function ◽  
Cell Model ◽  
Extracellular Vesicle ◽  
Alpha Synuclein ◽  
Proteinase K ◽  
In Vivo Studies

Abstract Aim We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson’s disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model. Methods The acute effects of single-dose treatment with DDL-112 on interleukin-1β-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined. Results/discussion In the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.

scholarly journals C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease

2018 ◽  
Vol 17 (1) ◽  
pp. 14-21 ◽  
Author(s):  
Abdelrahman Ibrahim Abushouk ◽  
Ahmed Negida ◽  
Rasha Abdelsalam Elshenawy ◽  
Hossam Zein ◽  
Ali M. Hammad ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Drug Targets ◽  
Experimental Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Current Evidence ◽  
Future Research ◽  
Neuroprotective Effects ◽  
Human Trial

Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of neurodegeneration. However, due to lack of data about the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Recent evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathogenesis of PD. Through parkin inactivation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-Abl activation is involved in neurodegeneration and (2) c-Abl inhibition shows neuroprotective effects and prevents dopaminergic neuronal' death. Current evidence from experimental studies and the first in-human trial shows that c-Abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-Abl in PD pathogenesis and the findings of preclinical experiments and the first in-human trial. In addition, based on lessons from the last decade and current preclinical evidence, we provide recommendations for future research in this area.

scholarly journals Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates

2014 ◽  
Vol 263 ◽  
pp. 158-168 ◽  
Author(s):  
Marina A. Gruden ◽  
Tatiana V. Davydova ◽  
Victor B. Narkevich ◽  
Valentina G. Fomina ◽  
Chao Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Intranasal Administration ◽  
Disease Model ◽  
Alpha Synuclein ◽  
Neurochemical Correlates

scholarly journals The Hsc70 Disaggregation Machinery Removes Monomer Units Directly from α-Synuclein Fibril Ends

2020 ◽  
Author(s):  
Matthias M. Schneider ◽  
Saurabh Gautam ◽  
Therese W. Herling ◽  
Ewa Andrzejewska ◽  
Georg Krainer ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
De Novo ◽  
Dissociation Constants ◽  
Cellular Protein ◽  
Alpha Synuclein ◽  
Amyloid Formation ◽  
Nucleotide Exchange ◽  
Wide Range

AbstractMolecular chaperones contribute to the maintenance of cellular protein homeostasis through a wide range of mechanisms, including the assistance of de novo protein folding, the rescue of misfolded proteins, and the prevention of amyloid formation. Chaperones of the Hsp70 family have a striking capability of disaggregating otherwise irreversible aggregate structures such as amyloid fibrils that accumulate during the development of neurodegenerative diseases. However, the mechanisms of this key emerging functionality remain largely unknown. Here, we bring together microfluidic measurements with kinetic analysis and show that that the Hsp70 protein heat chock complement Hsc70 together with its two co-chaperones DnaJB1 and the nucleotide exchange factor Apg2 is able to completely reverse the aggregation process of alpha-synuclein, associated with Parkinson’s disease, back to its soluble monomeric state. Moreover, we show that this reaction proceeds with first order kinetics in a process where monomer units are taken off directly from the fibril ends. Our results demonstrate that all components of the chaperone triad are essential for fibril disaggregation. Lastly, we quantify the interactions between the three chaperones as well as between the chaperones and the fibrils in solution, yielding both binding stoichiometries and dissociation constants. Crucially, we find that the stoichiometry of Hsc70 binding to fibrils suggests Hsc70 clustering at the fibril ends. Taken together, our results show that the mechanism of action of the Hsc70–DnaJB1–Apg2 chaperone system in disaggregating α-synuclein fibrils involves the removal of monomer units without any intermediate fragmentation steps. These findings are fundamental to our understanding of the suppression of amyloid proliferation early in life and the natural clearance mechanisms of fibrillar deposits in Parkinson’s disease, and inform on the possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies and related neurodegenerative diseases.

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