scholarly journals Delayed Onset Muscle Soreness (DOMS): The Repeated Bout Effect and Chemotherapy-Induced Axonopathy May Help Explain the Dying-Back Mechanism in Amyotrophic Lateral Sclerosis and Other Neurodegenerative Diseases

2021 ◽  
Vol 11 (1) ◽  
pp. 108
Author(s):  
Balázs Sonkodi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Muscle Spindle ◽  
Muscle Soreness ◽  
Repeated Bout Effect ◽  
Sensory Afferents ◽  
Delayed Onset ◽  
Gate Control ◽  
Lateral Sclerosis ◽  
Repeated Bout

Delayed onset muscle soreness (DOMS) is hypothesized to be caused by glutamate excitotoxicity-induced acute compression axonopathy of the sensory afferents in the muscle spindle. Degeneration of the same sensory afferents is implicated in the disease onset and progression of amyotrophic lateral sclerosis (ALS). A series of “silent” acute compression proprioceptive axonopathies with underlying genetic/environmental factors, damaging eccentric contractions and the non-resolving neuroinflammatory process of aging could lead to ALS disease progression. Since the sensory terminals in the muscle spindle could not regenerate from the micro-damage in ALS, unlike in DOMS, the induced protective microcircuits and their long-term functional plasticity (the equivalent of the repeated bout effect in DOMS) will be dysfunctional. The acute stress invoking osteocalcin, bradykinin, COX1, COX2, GDNF, PGE2, NGF, glutamate and N-methyl-D-aspartate (NMDA) receptors are suggested to be the critical signalers of this theory. The repeated bout effect of DOMS and the dysfunctional microcircuits in ALS are suggested to involve several dimensions of memory and learning, like pain memory, inflammation, working and episodic memory. The spatial encoding of these memory dimensions is compromised in ALS due to blunt position sense from the degenerating proprioceptive axon terminals of the affected muscle spindles. Dysfunctional microcircuits progressively and irreversibly interfere with postural control, with motor command and locomotor circuits, deplete the neuroenergetic system, and ultimately interfere with life-sustaining central pattern generators in ALS. The activated NMDA receptor is suggested to serve the “gate control” function in DOMS and ALS in line with the gate control theory of pain. Circumvention of muscle spindle-loading could be a choice of exercise therapy in muscle spindle-affected neurodegenerative diseases.

scholarly journals Post Orgasmic Illness Syndrome (POIS) and Delayed Onset Muscle Soreness (DOMS): Do They Have Anything in Common?

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1867
Author(s):  
Balázs Sonkodi ◽  
Zsolt Kopa ◽  
Péter Nyirády
Keyword(s):  
Stress Response ◽  
Muscle Soreness ◽  
Acute Stress ◽  
Delayed Onset Muscle Soreness ◽  
Repeated Bout Effect ◽  
Delayed Onset ◽  
Secondary Tissue ◽  
Acute Stress Response ◽  
Primary Injury ◽  
Repeated Bout

Post orgasmic illness syndrome is a rare, mysterious condition with an unknown pathomechanism and uncertain treatment. The symptoms of post orgasmic illness syndrome last about 2–7 days after an ejaculation. The current hypothesis proposes that the primary injury in post orgasmic illness syndrome is an acute compression proprioceptive axonopathy in the muscle spindle, as is suspected in delayed onset muscle soreness. The terminal arbor degeneration-like lesion of delayed onset muscle soreness is theorized to be an acute stress response energy-depleted dysfunctional mitochondria-induced impairment of Piezo2 channels and glutamate vesicular release. The recurring symptoms of post orgasmic illness syndrome after each ejaculation are suggested to be analogous to the repeated bout effect of delayed onset muscle soreness. However, there are differences in the pathomechanism, mostly attributed to the extent of secondary tissue damage and to the extent of spermidine depletion. The spermidine depletion-induced differences are as follows: modulation of the acute stress response, flu-like symptoms, opioid-like withdrawal and enhanced deregulation of the autonomic nervous system. The longitudinal dimension of delayed onset muscle soreness, in the form of post orgasmic illness syndrome and the repeated bout effect, have cognitive and memory consequences, since the primary injury is learning and memory-related.

scholarly journals Therapeutic Assay with the Non-toxic C-Terminal Fragment of Tetanus Toxin (TTC) in Transgenic Murine Models of Prion Disease

2021 ◽  
Author(s):  
Marina Betancor ◽  
Laura Moreno-Martínez ◽  
Óscar López-Pérez ◽  
Alicia Otero ◽  
Adelaida Hernaiz ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Prion Disease ◽  
Tetanus Toxin ◽  
Neuronal Survival ◽  
Prion Diseases ◽  
Cellular Prion Protein ◽  
Murine Models ◽  
Terminal Fragment ◽  
Lateral Sclerosis

AbstractThe non-toxic C-terminal fragment of the tetanus toxin (TTC) has been described as a neuroprotective molecule since it binds to Trk receptors and activates Trk-dependent signaling, activating neuronal survival pathways and inhibiting apoptosis. Previous in vivo studies have demonstrated the ability of this molecule to increase mice survival, inhibit apoptosis and regulate autophagy in murine models of neurodegenerative diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy. Prion diseases are fatal neurodegenerative disorders in which the main pathogenic event is the conversion of the cellular prion protein (PrPC) into an abnormal and misfolded isoform known as PrPSc. These diseases share different pathological features with other neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson’s disease or Alzheimer’s disease. Hitherto, there are no effective therapies to treat prion diseases. Here, we present a pilot study to test the therapeutic potential of TTC to treat prion diseases. C57BL6 wild-type mice and the transgenic mice Tg338, which overexpress PrPC, were intracerebrally inoculated with scrapie prions and then subjected to a treatment consisting of repeated intramuscular injections of TTC. Our results indicate that TTC displays neuroprotective effects in the murine models of prion disease reducing apoptosis, regulating autophagy and therefore increasing neuronal survival, although TTC did not increase survival time in these models.

scholarly journals Proline/arginine dipeptide repeat polymers derail protein folding in amyotrophic lateral sclerosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria Babu ◽  
Filippo Favretto ◽  
Alain Ibáñez de Opakua ◽  
Marija Rankovic ◽  
Stefan Becker ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Folding ◽  
Neurodegenerative Diseases ◽  
Catalyst Activity ◽  
Coding Region ◽  
Prolyl Isomerase ◽  
X Ray Crystallography ◽  
Hexanucleotide Repeat ◽  
Lateral Sclerosis ◽  
Dipeptide Repeat

AbstractAmyotrophic lateral sclerosis and frontotemporal dementia are two neurodegenerative diseases with overlapping clinical features and the pathological hallmark of cytoplasmic deposits of misfolded proteins. The most frequent cause of familial forms of these diseases is a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene that is translated into dipeptide repeat polymers. Here we show that proline/arginine repeat polymers derail protein folding by sequestering molecular chaperones. We demonstrate that proline/arginine repeat polymers inhibit the folding catalyst activity of PPIA, an abundant molecular chaperone and prolyl isomerase in the brain that is altered in amyotrophic lateral sclerosis. NMR spectroscopy reveals that proline/arginine repeat polymers bind to the active site of PPIA. X-ray crystallography determines the atomic structure of a proline/arginine repeat polymer in complex with the prolyl isomerase and defines the molecular basis for the specificity of disease-associated proline/arginine polymer interactions. The combined data establish a toxic mechanism that is specific for proline/arginine dipeptide repeat polymers and leads to derailed protein homeostasis in C9orf72-associated neurodegenerative diseases.

scholarly journals Paraoxonase Role in Human Neurodegenerative Diseases

Antioxidants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 11
Author(s):  
Cadiele Oliana Reichert ◽  
Debora Levy ◽  
Sergio P. Bydlowski
Keyword(s):  
Oxidative Stress ◽  
Multiple Sclerosis ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
High Density Lipoprotein ◽  
Density Lipoprotein ◽  
Structural Homology ◽  
Redox Systems ◽  
Genetic Cluster ◽  
Lateral Sclerosis

The human body has biological redox systems capable of preventing or mitigating the damage caused by increased oxidative stress throughout life. One of them are the paraoxonase (PON) enzymes. The PONs genetic cluster is made up of three members (PON1, PON2, PON3) that share a structural homology, located adjacent to chromosome seven. The most studied enzyme is PON1, which is associated with high density lipoprotein (HDL), having paraoxonase, arylesterase and lactonase activities. Due to these characteristics, the enzyme PON1 has been associated with the development of neurodegenerative diseases. Here we update the knowledge about the association of PON enzymes and their polymorphisms and the development of multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and Parkinson’s disease (PD).

scholarly journals Bile Acids Reduce Prion Conversion, Reduce Neuronal Loss, and Prolong Male Survival in Models of Prion Disease

2015 ◽  
Vol 89 (15) ◽  
pp. 7660-7672 ◽  
Author(s):  
Leonardo M. Cortez ◽  
Jody Campeau ◽  
Grant Norman ◽  
Marian Kalayil ◽  
Jacques Van der Merwe ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Bile Acids ◽  
Prion Disease ◽  
Prion Diseases ◽  
Neuronal Loss ◽  
Disease Models ◽  
Orally Bioavailable ◽  
Prion Conversion ◽  
Lateral Sclerosis

ABSTRACTPrion diseases are fatal neurodegenerative disorders associated with the conversion of cellular prion protein (PrPC) into its aberrant infectious form (PrPSc). There is no treatment available for these diseases. The bile acids tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA) have been recently shown to be neuroprotective in other protein misfolding disease models, including Parkinson's, Huntington's and Alzheimer's diseases, and also in humans with amyotrophic lateral sclerosis. Here, we studied the therapeutic efficacy of these compounds in prion disease. We demonstrated that TUDCA and UDCA substantially reduced PrP conversion in cell-free aggregation assays, as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of PrPScseeding ability, rather than an effect on PrPC. We also demonstrated the ability of TUDCA and UDCA to reduce neuronal loss in prion-infected cerebellar slice cultures. UDCA treatment reduced astrocytosis and prolonged survival in RML prion-infected mice. Interestingly, these effects were limited to the males, implying a gender-specific difference in drug metabolism. Beyond effects on PrPSc, we found that levels of phosphorylated eIF2α were increased at early time points, with correlated reductions in postsynaptic density protein 95. As demonstrated for other neurodegenerative diseases, we now show that TUDCA and UDCA may have a therapeutic role in prion diseases, with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans, make these compounds promising alternatives for the treatment of prion diseases.IMPORTANCEPrion diseases are fatal neurodegenerative diseases that are transmissible to humans and other mammals. There are no disease-modifying therapies available, despite decades of research. Treatment targets have included inhibition of protein accumulation, clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multimodal mechanism, acting on different targets, would be ideal. TUDCA and UDCA are bile acids that may fulfill this dual role. Previous studies have demonstrated their neuroprotective effects in several neurodegenerative disease models, and we now demonstrate that this effect occurs in prion disease, with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier, and U.S. Food and Drug Administration-approved for use in humans with primary biliary cirrhosis. They have recently been proven efficacious in human amyotrophic lateral sclerosis. Therefore, these compounds are promising options for the treatment of prion diseases.

scholarly journals Evidence for GRN as part of a neuroinflammatory mechanism connecting common neurodegenerative diseases

2020 ◽  
Author(s):  
Mike A. Nalls ◽  
Cornelis Blauwendraat ◽  
Lana Sargent ◽  
Dan Vitale ◽  
Hampton Leonard ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Genetic Risk ◽  
Association Studies ◽  
Molecular Data ◽  
Genome Wide Association Studies ◽  
Data Types ◽  
Genome Wide ◽  
Trait Locus ◽  
Lateral Sclerosis

SUMMARYBackgroundPrevious research using genome wide association studies (GWAS) has identified variants that may contribute to lifetime risk of multiple neurodegenerative diseases. However, whether there are common mechanisms that link neurodegenerative diseases is uncertain. Here, we focus on one gene, GRN, encoding progranulin, and the potential mechanistic interplay between genetic risk, gene expression in the brain and inflammation across multiple common neurodegenerative diseases.MethodsWe utilized GWAS, expression quantitative trait locus (eQTL) mapping and Bayesian colocalization analyses to evaluate potential causal and mechanistic inferences. We integrate various molecular data types from public resources to infer disease connectivity and shared mechanisms using a data driven process.FindingseQTL analyses combined with GWAS identified significant functional associations between increasing genetic risk in the GRN region and decreased expression of the gene in Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis. Additionally, colocalization analyses show a connection between blood based inflammatory biomarkers relating to platelets and GRN expression in the frontal cortex.InterpretationGRN expression mediates neuroinflammation function related to general neurodegeneration. This analysis suggests shared mechanisms for Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis.FundingNational Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J. Fox Foundation.

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