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

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.

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Alpha-synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

Biology Open ◽

10.1242/bio.054338 ◽

2020 ◽

Vol 9 (10) ◽

pp. bio054338

Author(s):

Anila Iqbal ◽

Marta Baldrighi ◽

Jennifer N. Murdoch ◽

Angeleen Fleming ◽

Christopher J. Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Intracellular Transport ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Types ◽

Alpha Synuclein ◽

Microtubule Network ◽

Main Component

ABSTRACTProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the accumulation of α-synuclein, the main component of Lewy bodies found in Parkinson's disease. Aggresomes are closely-related, cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organise the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to functional deficits and neuronal cell death in Parkinson's disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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Alpha synuclein aggresomes inhibit ciliogenesis and multiple functions of the centrosome

10.1101/2019.12.20.884643 ◽

2019 ◽

Author(s):

Anila Iqbal ◽

Marta Baldrighi ◽

Jennifer N. Murdoch ◽

Angeleen Fleming ◽

Christopher J. Wilkinson

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Intracellular Transport ◽

Neuronal Cell Death ◽

Lewy Bodies ◽

Neuronal Cell ◽

Cell Types ◽

Alpha Synuclein ◽

Microtubule Network

AbstractProtein aggregates are the pathogenic hallmarks of many different neurodegenerative diseases and include the Lewy bodies found in Parkinson’s disease. Aggresomes are closely-related cellular accumulations of misfolded proteins. They develop in a juxtanuclear position, adjacent to the centrosome, the microtubule organizing centre of the cell, and share some protein components. Despite the long-standing observation that aggresomes/Lewy bodies and the centrosome sit side-by-side in the cell, no studies have been done to see whether these protein accumulations impede the organelle function. We investigated whether the formation of aggresomes affected key centrosome functions: its ability to organize the microtubule network and to promote cilia formation. We find that when aggresomes are present, neuronal cells are unable to organise their microtubule network. New microtubules are not nucleated and extended, and the cells fail to respond to polarity cues. Since dopaminergic neurons are polarised, ensuring correct localisation of organelles and the effective intracellular transport of neurotransmitter vesicles, loss of centrosome activity could contribute to loss of dopaminergic function and neuronal cell death in Parkinson’s disease. In addition, we provide evidence that many cell types, including dopaminergic neurons, cannot form cilia when aggresomes are present, which would affect their ability to receive extracellular signals.

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

10.1101/2020.08.30.274050 ◽

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.

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

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527316666170602101538 ◽

2018 ◽

Vol 17 (1) ◽

pp. 14-21 ◽

Cited By ~ 13

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.

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Functions of Intracellular Alpha-Synuclein in Microglia: Implications for Parkinson’s Disease Risk

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.759571 ◽

2021 ◽

Vol 15 ◽

Author(s):

Alix Booms ◽

Gerhard A. Coetzee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Significant Risk ◽

Physiological Role ◽

Significant Risk Factor ◽

Cell Types ◽

Alpha Synuclein ◽

Vesicle Formation ◽

Immune Functions

Alpha-synuclein accumulation in dopaminergic neurons is one of the primary features of Parkinson’s disease (PD). Despite its toxic properties during PD, alpha-synuclein has some important physiological functions. Although the activity of the protein has been extensively studied in neurons, the protein is also expressed in other cell types including immune cells and glia. Genetic studies show that mutations in synuclein alpha (SNCA), the gene that encodes alpha-synuclein, and alterations in its expression levels are a significant risk factor for PD, which likely impact the functions of a broad range of cell types. The consequences of altered SNCA expression in other cell types is beginning to be explored. Microglia, the primary macrophage population in the Central Nervous System (CNS), for example, are affected by variations in alpha-synuclein levels and functions. Studies suggest that deviations of alpha-synuclein’s normal activity influence hematopoiesis, the process that gives rise to microglia, and microglia’s immune functions. Alpha-synuclein levels also dictate the efficiency of SNARE-mediated vesicle formation, which could influence autophagy and cytokine release in microglia. Starting from the time of conception, these effects could impact one’s risk for developing PD. Further studies are needed to determine the physiological role of alpha-synuclein and how the protein is affected during PD in non-neuronal cells such as microglia. In this review we will discuss the known roles of alpha-synuclein in differentiation, immune responses, and vesicle formation, with insights into how abnormal alpha-synuclein expression and activity are linked to altered functions of microglia during PD.

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