The Catecholaldehyde Hypothesis for the Pathogenesis of Catecholaminergic Neurodegeneration: What We Know and What We Do Not Know

3,4-Dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson’s disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally, DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (αS), a major component of Lewy bodies. DOPAL potently oligomerizes αS, and αS oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward the MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intraneuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with αS, and vice versa, is poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intraneuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

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Alpha-Synuclein Preserves Mitochondrial Fusion and Function in Neuronal Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4246350 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Gaia Faustini ◽

Elena Marchesan ◽

Laura Zonta ◽

Federica Bono ◽

Emanuela Bottani ◽

...

Keyword(s):

Cortical Neurons ◽

Neurodegenerative Disorder ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Physical Interaction ◽

Primary Cortical Neurons ◽

Altered Expression ◽

Extracellular Flux ◽

Mitochondrial Functions ◽

And Function

Dysregulations of mitochondria with alterations in trafficking and morphology of these organelles have been related to Parkinson’s disease (PD), a neurodegenerative disorder characterized by brain accumulation of Lewy bodies (LB), intraneuronal inclusions mainly composed of α-synuclein (α-syn) fibrils. Experimental evidence supports that α-syn pathological aggregation can negatively impinge on mitochondrial functions suggesting that this protein may be crucially involved in the control of mitochondrial homeostasis. The aim of this study was to assay this hypothesis by analyzing mitochondrial function and morphology in primary cortical neurons from C57BL/6JOlaHsd α-syn null and C57BL/6J wild-type (wt) mice. Primary cortical neurons from mice lacking α-syn showed decreased respiration capacity measured with a Seahorse XFe24 Extracellular Flux Analyzer. In addition, morphological Airyscan superresolution microscopy showed the presence of fragmented mitochondria while real-time PCR and western blot confirmed altered expression of proteins involved in mitochondrial shape modifications in the primary cortical neurons of α-syn null mice. Transmission electron microscopy (TEM) studies showed that α-syn null neurons exhibited impaired mitochondria-endoplasmic reticulum (ER) physical interaction. Specifically, we identified a decreased number of mitochondria-ER contacts (MERCs) paralleled by a significant increase in ER-mitochondria distance (i.e., MERC length). These findings support that α-syn physiologically preserves mitochondrial functions and homeostasis. Studying α-syn/mitochondria interplay in health and disease is thus pivotal for understanding their involvement in PD and other LB disorders.

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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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Neurons and Glia Interplay in α-Synucleinopathies

International Journal of Molecular Sciences ◽

10.3390/ijms22094994 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4994

Author(s):

Panagiota Mavroeidi ◽

Maria Xilouri

Keyword(s):

Glial Cells ◽

Current Knowledge ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Lewy Neurites ◽

Cytoplasmic Inclusions ◽

Glial Cytoplasmic Inclusions ◽

Glial Function ◽

Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

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Multiple system atrophy-associated oligodendroglial protein p25α stimulates formation of novel α-synuclein strain with enhanced neurodegenerative potential

Acta Neuropathologica ◽

10.1007/s00401-021-02316-0 ◽

2021 ◽

Author(s):

Nelson Ferreira ◽

Hjalte Gram ◽

Zachary A. Sorrentino ◽

Emil Gregersen ◽

Sissel Ida Schmidt ◽

...

Keyword(s):

Multiple System Atrophy ◽

Protein Misfolding ◽

Resonance Energy Transfer ◽

Lewy Bodies ◽

Resonance Energy ◽

Alpha Synuclein ◽

Striatal Neurons ◽

End Stage ◽

Intracellular Aggregates

AbstractPathology consisting of intracellular aggregates of alpha-Synuclein (α-Syn) spread through the nervous system in a variety of neurodegenerative disorders including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The discovery of structurally distinct α-Syn polymorphs, so-called strains, supports a hypothesis where strain-specific structures are templated into aggregates formed by native α-Syn. These distinct strains are hypothesised to dictate the spreading of pathology in the tissue and the cellular impact of the aggregates, thereby contributing to the variety of clinical phenotypes. Here, we present evidence of a novel α-Syn strain induced by the multiple system atrophy-associated oligodendroglial protein p25α. Using an array of biophysical, biochemical, cellular, and in vivo analyses, we demonstrate that compared to α-Syn alone, a substoichiometric concentration of p25α redirects α-Syn aggregation into a unique α-Syn/p25α strain with a different structure and enhanced in vivo prodegenerative properties. The α-Syn/p25α strain induced larger inclusions in human dopaminergic neurons. In vivo, intramuscular injection of preformed fibrils (PFF) of the α-Syn/p25α strain compared to α-Syn PFF resulted in a shortened life span and a distinct anatomical distribution of inclusion pathology in the brain of a human A53T transgenic (line M83) mouse. Investigation of α-Syn aggregates in brain stem extracts of end-stage mice demonstrated that the more aggressive phenotype of the α-Syn/p25α strain was associated with an increased load of α-Syn aggregates based on a Förster resonance energy transfer immunoassay and a reduced α-Syn aggregate seeding activity based on a protein misfolding cyclic amplification assay. When injected unilaterally into the striata of wild-type mice, the α-Syn/p25α strain resulted in a more-pronounced motoric phenotype than α-Syn PFF and exhibited a “tropism” for nigro-striatal neurons compared to α-Syn PFF. Overall, our data support a hypothesis whereby oligodendroglial p25α is responsible for generating a highly prodegenerative α-Syn strain in multiple system atrophy.

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ALPHA SYNUCLEIN IMMUNOREACTIVITY IN DEMENTIA WITH LEWY BODIES

Journal of Neuropathology & Experimental Neurology ◽

10.1097/00005072-199905000-00188 ◽

1999 ◽

Vol 58 (5) ◽

pp. 553

Author(s):

E Gómez-Tortosa ◽

K L Newell ◽

M C Irizarry ◽

M Albert ◽

J H Growdon ◽

...

Keyword(s):

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein

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Black Cumin (Nigella sativa L.): A Comprehensive Review on Phytochemistry, Health Benefits, Molecular Pharmacology, and Safety

Nutrients ◽

10.3390/nu13061784 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1784

Author(s):

Md. Abdul Hannan ◽

Md. Ataur Rahman ◽

Abdullah Al Mamun Sohag ◽

Md. Jamal Uddin ◽

Raju Dash ◽

...

Keyword(s):

Nigella Sativa ◽

Health Benefits ◽

Underlying Mechanism ◽

Future Research ◽

Molecular Pharmacology ◽

Active Components ◽

Drug Induced ◽

Current Effort ◽

Black Cumin ◽

Pharmaceutical Industries

Mounting evidence support the potential benefits of functional foods or nutraceuticals for human health and diseases. Black cumin (Nigella sativa L.), a highly valued nutraceutical herb with a wide array of health benefits, has attracted growing interest from health-conscious individuals, the scientific community, and pharmaceutical industries. The pleiotropic pharmacological effects of black cumin, and its main bioactive component thymoquinone (TQ), have been manifested by their ability to attenuate oxidative stress and inflammation, and to promote immunity, cell survival, and energy metabolism, which underlie diverse health benefits, including protection against metabolic, cardiovascular, digestive, hepatic, renal, respiratory, reproductive, and neurological disorders, cancer, and so on. Furthermore, black cumin acts as an antidote, mitigating various toxicities and drug-induced side effects. Despite significant advances in pharmacological benefits, this miracle herb and its active components are still far from their clinical application. This review begins with highlighting the research trends in black cumin and revisiting phytochemical profiles. Subsequently, pharmacological attributes and health benefits of black cumin and TQ are critically reviewed. We overview molecular pharmacology to gain insight into the underlying mechanism of health benefits. Issues related to pharmacokinetic herb–drug interactions, drug delivery, and safety are also addressed. Identifying knowledge gaps, our current effort will direct future research to advance potential applications of black cumin and TQ in health and diseases.

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[P1-243]: ALPHA-SYNUCLEIN SPECIES AS POTENTIAL CSF BIOMARKERS FOR DEMENTIA WITH LEWY BODIES

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.063 ◽

2017 ◽

Vol 13 (7S_Part_7) ◽

pp. P338-P338 ◽

Cited By ~ 2

Author(s):

Inger van Steenoven ◽

Nour K. Majbour ◽

Nishant N. Vaikath ◽

Henk W. Berendse ◽

Wiesje M. van der Flier ◽

...

Keyword(s):

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Csf Biomarkers

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Are lysosomes potential therapeutic targets for Parkinson’s disease?

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527320666210809123630 ◽

2021 ◽

Vol 20 ◽

Author(s):

A. Petese ◽

V. Cesaroni ◽

S. Cerri ◽

F. Blandini

Keyword(s):

Neurodegenerative Disorder ◽

Association Studies ◽

Lewy Bodies ◽

Alpha Synuclein ◽

Genome Wide Association Studies ◽

Lysosomal Dysfunction ◽

Genome Wide ◽

Nigrostriatal Neurons ◽

Disease Modifying Treatment ◽

Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

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