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

Author(s):  
Renu Minda

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.

Author(s):  
Renu Minda

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.


2020 ◽  
Vol 44 (3) ◽  
pp. 241-249
Author(s):  
Yoshiaki Omura

While a visiting Professor at the University of Paris, VI (formerly Sorvonne) more than 40 years ago, the Author became very good friends with Dr. Paul Nogier who periodically gave seminars and workshops in Paris. After the author diagnosed his cervical problem & offered him simple help, Dr. Nogier asked the Author to present lectures and demonstrations on the effects of ear stimulation, namely the effects of acupuncture & electrical stimulation of the ear lobules. It is only now, in 2019 that we have discovered 2–5 minute high frequency stimulation of the ear lobule inhibits cancer activity for 1– 4 hours post stimulation. Although the procedure is extremely simple. First take optimal dose of Vitamin D3, which has the most essential 10 unique beneficial factors required for every human cell activity. Next, apply high frequency stimulation to ear lobule while the worst ear lobule is held by all fingers with vibrator directly touching the surface of the worst ear lobule, preferably after patient repeatedly takes optimal dose of Vitamin D3. When the worst ear lobule is held between thumb & index fingers and applying mechanical stimulation of 250 ~ 500 mechanical vibration/second for 2 ~ 5 minutes using an electrical vibrator, there is rapid disappearance of cancer activity in both the brain and rest of the body for short time duration 1 ~ 4 hours. The effect often increases by additional pressure by holding fingers. As of May 2019, the Author found that many people from various regions of the world developed early stages of multiple cancers. For evaluation of this study, U. S. patented Bi-Digital O-Ring Test (BDORT) was used which was developed by the Author while doing his Graduate experimental physics research at Colombia University. BDORT was found to be most essential for determining the beneficial effects as well as harmful effects of any substance or treatment. Using BDORT, Author was the first to recognize severe increasing mid-backache was an early sign of pancreatic cancer of President of New York State Board of Medicine after top pain specialists failed to detect the cause after 3 years of effort, while the BDORT showed early stages of cancer whereas conventional X-Ray of the pancreas did not show any cancer image until 2 months after Author detected with BDORT. For example, the optimal dose of the banana is usually about 2.0 - 2.5 millimeters cross section of the banana. A whole banana is more than 50 ~ 100 times the optimal dose. Any substance eaten in more than 25 times of its optimal dose becomes highly toxic and creates DNA mutations which can cause multiple malignancies in the presence of strong electro-magnetic field. With standard medication given by doctor, patients often become sick and they are unable to reduce body weight, unless medication is reduced or completely stopped. When the amount of zinc is very high, DNA often becomes unstable and multiple cancers can grow rapidly in the presence of strong electromagnetic field. Large amount of Vitamin C from regular orange or orange juice inhibit the most important Vitamin D3 effects. At least 3 kinds of low Vitamin C oranges will not inhibit Vitamin D3. Since B12 particularly methyl cobalamin which is a red small tablet is known to improve brain circulation very significantly we examined its effect within 20 seconds of oral intake we found the following very significant changes. Acetylcholine in both sides of the brain often increases over 4,500 ng. Longevity gene Sirtuin 1 level increases significantly for short time of few hours. Thymosin α1 and Thymosinβ4 both increase to over 1500 ng from 20 ng or less.


2021 ◽  
Vol 22 (11) ◽  
pp. 5999
Author(s):  
David S. Goldstein

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.


2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri

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.


1957 ◽  
Vol 40 (3) ◽  
pp. 435-450 ◽  
Author(s):  
David P. C. Lloyd

An assemblage of individual motoneurons constituting a synthetic motoneuron pool has been studied from the standpoint of relating monosynaptic reflex responses to frequency of afferent stimulation. Intensity of low frequency depression is not a simple function of transmitter potentiality. As frequency of stimulation increases from 3 per minute to 10 per second, low frequency depression increases in magnitude. Between 10 and approximately 60 per second low frequency depression apparently diminishes and subnormality becomes a factor in causing depression. At frequencies above 60 per second temporal summation occurs, but subnormality limits the degree of response attainable by summation. At low stimulation frequencies rhythm is determined by stimulation frequency. Interruptions of rhythmic firing depend solely upon temporal fluctuation of excitability. At high frequency of stimulation rhythm is determined by subnormality rather than inherent rhythmicity, and excitability fluctuation leads to instability of response rhythm. In short, whatever the stimulation frequency, random excitability fluctuation is the factor disrupting rhythmic response. Monosynaptic reflex response latency is stable during high frequency stimulation as it is in low frequency stimulation provided a significant extrinsic source of random bombardment is not present. In the presence of powerful random bombardment discharge may become random with respect to monosynaptic afferent excitation provided the latter is feeble. When this occurs it does so equally at low frequency and high frequency. Thus temporal summation is not a necessary factor. There is, then, no remaining evidence to suggest that the agency for temporal summation in the monosynaptic system becomes a transmitting agency in its own right.


Author(s):  
Nelson Ferreira ◽  
Hjalte Gram ◽  
Zachary A. Sorrentino ◽  
Emil Gregersen ◽  
Sissel Ida Schmidt ◽  
...  

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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