scholarly journals Role of alpha-Synuclein in Cell Biology: A Hypothesis

2021 ◽  
Author(s):  
Renu Minda
Keyword(s):  
Parkinson Disease ◽  
Membrane Fluidity ◽  
Cell Biology ◽  
Physiological Function ◽  
Alpha Synuclein ◽  
Carnot Cycle ◽  
Pathological Conditions

I wish to suggest a hypothesis regarding the physiological function of alpha-synuclein, a protein implicated in Parkinson disease, whose cell biology is still debated. The essence is the concept of Carnot cycle of refrigeration in which membrane fluidity depends on the heat produced by mitochondria. The hypothesis has the potential to explain the diverse phenotypes attributed to alpha-synuclein under both physiological and pathological conditions.

scholarly journals α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

2021 ◽  
Author(s):  
Alberto Delaidelli ◽  
Mette Richner ◽  
Lixiang Jiang ◽  
Amelia van der Laan ◽  
Ida Bergholdt Jul Christiansen ◽  
...  
Keyword(s):  
Nervous System ◽  
Parkinson Disease ◽  
Redox Homeostasis ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Motor Nucleus ◽  
Related Factor ◽  
Dorsal Motor Nucleus ◽  
Anti Oxidant

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleionpathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2) is recognized as the master regulator of cellular anti-oxidant response, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, Prnp-SNCA*Ala53Thr), which manifest widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

Role of a-Synuclein in Cell Biology: A Hypothesis and its Implications in Neurodegenerative Diseases

2022 ◽  
Author(s):  
Renu Minda
Keyword(s):  
Phase Transition ◽  
Cell Biology ◽  
Physiological Function ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
High Frequency Stimulation ◽  
Metabolic Reaction ◽  
Rapid Phase ◽  
Ample Evidence ◽  
Frequency Stimulation

I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is to modulate membrane fluidity by a process wherein it goes through a conformation cycle driven by a flux of energy from mitochondria. It is the range of toxic a-syn produced during aberrant phase transition reaction that is responsible for pathology, not the normal a-syn that reenters the conformation cycle, thereby, resolving the paradox of the Janus-face of a-syn.

scholarly journals Alpha-Synuclein and Mitochondrial Dysfunction in Parkinson’s Disease: The Emerging Role of VDAC

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 718
Author(s):  
Pierpaolo Risiglione ◽  
Federica Zinghirino ◽  
Maria Carmela Di Rosa ◽  
Andrea Magrì ◽  
Angela Messina
Keyword(s):  
Parkinson’S Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Anion Channel ◽  
Alpha Synuclein ◽  
Voltage Dependent Anion Channel ◽  
Cytosolic Proteins ◽  
Pathological Conditions ◽  
Voltage Dependent

Alpha-Synuclein (αSyn) is a protein whose function is still debated, as well as its role in modulation of mitochondrial function in both physiological and pathological conditions. Mitochondrial porins or Voltage-Dependent Anion Channel (VDAC) proteins are the main gates for ADP/ATP and various substrates towards the organelle. Furthermore, they act as a mitochondrial hub for many cytosolic proteins, including αSyn. This review analyzes the main aspects of αSyn-mitochondria interaction, focusing on the role of VDAC and its emerging involvement in the pathological processes.

scholarly journals α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Alberto Delaidelli ◽  
Mette Richner ◽  
Lixiang Jiang ◽  
Amelia van der Laan ◽  
Ida Bergholdt Jul Christiansen ◽  
...  
Keyword(s):  
Nervous System ◽  
Parkinson Disease ◽  
Redox Homeostasis ◽  
Alpha Synuclein ◽  
Experimental Models ◽  
Motor Nucleus ◽  
Related Factor ◽  
Dorsal Motor Nucleus ◽  
Anti Oxidant

AbstractCircumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as ‘the master regulator of cellular anti-oxidant response’, both under physiological as well as in pathological conditions. Using immunohistochemical analyses, we show a robust nuclear NRF2 accumulation in post-mortem PD midbrain, detected by NRF2 phosphorylation on the serine residue 40 (nuclear active p-NRF2, S40). Curated gene expression analyses of four independent publicly available microarray datasets revealed considerable alterations in NRF2-responsive genes in the disease affected regions in PD, including substantia nigra, dorsal motor nucleus of vagus, locus coeruleus and globus pallidus. To further examine the putative role of pathological aSyn accumulation on nuclear NRF2 response, we employed a transgenic mouse model of synucleionopathy (M83 line, expressing the mutant human A53T aSyn), which manifests widespread aSyn pathology (phosphorylated aSyn; S129) in the nervous system following intramuscular inoculation of exogenous fibrillar aSyn. We observed strong immunodetection of nuclear NRF2 in neuronal populations harboring p-aSyn (S129), and found an aberrant anti-oxidant and inflammatory gene response in the affected neuraxis. Taken together, our data support the notion that pathological aSyn accumulation impairs the redox homeostasis in nervous system, and boosting neuronal anti-oxidant response is potentially a promising approach to mitigate neurodegeneration in PD and related diseases.

Dietary Carotenoids in Managing Metabolic Syndrome and Role of PPARs in the Process

2020 ◽  
Vol 16 (6) ◽  
pp. 846-853
Author(s):  
Raghunandan Purohith ◽  
Nagendra P.M. Nagalingaswamy ◽  
Nanjunda S. Shivananju
Keyword(s):  
Metabolic Syndrome ◽  
Dietary Intervention ◽  
Bioactive Constituents ◽  
Dietary Antioxidants ◽  
Predisposing Factor ◽  
Beneficial Effects ◽  
Pathological Conditions ◽  
Established Relationship ◽  
Comprehensive Study

Metabolic syndrome is a collective term that denotes disorder in metabolism, symptoms of which include hyperglycemia, hyperlipidemia, hypertension, and endothelial dysfunction. Diet is a major predisposing factor in the development of metabolic syndrome, and dietary intervention is necessary for both prevention and management. The bioactive constituents of food play a key role in this process. Micronutrients such as vitamins, carotenoids, amino acids, flavonoids, minerals, and aromatic pigment molecules found in fruits, vegetables, spices, and condiments are known to have beneficial effects in preventing and managing metabolic syndrome. There exists a well-established relationship between oxidative stress and major pathological conditions such as inflammation, metabolic syndrome, and cancer. Consequently, dietary antioxidants are implicated in the remediation of these complications. The mechanism of action and targets of dietary antioxidants as well as their effects on related pathways are being extensively studied and elucidated in recent times. This review attempts a comprehensive study of the role of dietary carotenoids in alleviating metabolic syndromewith an emphasis on molecular mechanism-in the light of recent advances.

The Role of Androgen Under Normal and Pathological Conditions in Sebaceous Glands: The Possibility of Target Therapy

2016 ◽  
Vol 9 (4) ◽  
pp. 311-319 ◽  
Author(s):  
Abdullah Azmahani ◽  
Yasuhiro Nakamura ◽  
Keely M. McNamara ◽  
Hironobu Sasano
Keyword(s):  
Target Therapy ◽  
Sebaceous Glands ◽  
Pathological Conditions

scholarly journals Physical Exercise and Cardiac Repair: The Potential Role of Nitric Oxide in Boosting Stem Cell Regenerative Biology

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1002
Author(s):  
Fabiola Marino ◽  
Mariangela Scalise ◽  
Eleonora Cianflone ◽  
Luca Salerno ◽  
Donato Cappetta ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cell ◽  
Physical Exercise ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Heart Function ◽  
Stem Cell Biology ◽  
Myocardial Repair ◽  
Beneficial Effects

Over the years strong evidence has been accumulated showing that aerobic physical exercise exerts beneficial effects on the prevention and reduction of cardiovascular risk. Exercise in healthy subjects fosters physiological remodeling of the adult heart. Concurrently, physical training can significantly slow-down or even reverse the maladaptive pathologic cardiac remodeling in cardiac diseases, improving heart function. The underlying cellular and molecular mechanisms of the beneficial effects of physical exercise on the heart are still a subject of intensive study. Aerobic activity increases cardiovascular nitric oxide (NO) released mainly through nitric oxidase synthase 3 activity, promoting endothelium-dependent vasodilation, reducing vascular resistance, and lowering blood pressure. On the reverse, an imbalance between increasing free radical production and decreased NO generation characterizes pathologic remodeling, which has been termed the “nitroso-redox imbalance”. Besides these classical evidence on the role of NO in cardiac physiology and pathology, accumulating data show that NO regulate different aspects of stem cell biology, including survival, proliferation, migration, differentiation, and secretion of pro-regenerative factors. Concurrently, it has been shown that physical exercise generates physiological remodeling while antagonizes pathologic remodeling also by fostering cardiac regeneration, including new cardiomyocyte formation. This review is therefore focused on the possible link between physical exercise, NO, and stem cell biology in the cardiac regenerative/reparative response to physiological or pathological load. Cellular and molecular mechanisms that generate an exercise-induced cardioprotective phenotype are discussed in regards with myocardial repair and regeneration. Aerobic training can benefit cells implicated in cardiovascular homeostasis and response to damage by NO-mediated pathways that protect stem cells in the hostile environment, enhance their activation and differentiation and, in turn, translate to more efficient myocardial tissue regeneration. Moreover, stem cell preconditioning by and/or local potentiation of NO signaling can be envisioned as promising approaches to improve the post-transplantation stem cell survival and the efficacy of cardiac stem cell therapy.

Exploration of the role of whole exome sequencing variants in -associated Parkinson disease

2021 ◽  
Vol 132 (2) ◽  
pp. S113
Author(s):  
Elizabeth Geena Woo ◽  
Frank Donovan ◽  
Barbara Stubblefield ◽  
Settara Chandrasekharappa ◽  
Grisel Lopez ◽  
...  
Keyword(s):  
Parkinson Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome
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