This crucial discovery points to a common cause of both neurological diseases such as dementia and motor neuron diseases such as ALS and Parkinson disease.
Currently, most scientists do not see a link between ALS and Alzheimer's disease, Parkinson's disease, frontotemporal dementia (FTD), or other dementias. The medical community has for decades attributed symptoms of some of these disorders to the accumulation of amyloid plaque in the brain.
New research confirms the relevance of a certain neurotoxic pathway, TDP-43. The article also confirms TDP-43 inhibition as a viable therapeutic option for the treatment of neurologic disorders, including Alzheimer disease.
Xinglong Wang, PhD, assistant professor of pathology at Case Western Reserve University School of Medicine, may be a pioneer who forces scientists to discard years of medical dogma and leads clinicians to significantly improved treatments.
Wang received a call from a desperate father of a middle-aged son with amyotrophic lateral sclerosis (ALS) "Can you help save my son's life?" the parent asked.
On that day, Wang, felt the weight of human suffering on his shoulders. But this is a weight that Wang can bear. He may be in the process of entirely upending the current scientific view of ALS and other neuronal diseases.
Wang published a paper in Nature Medicine (2016) in which he and his colleagues had shown that the symptoms of ALS in mice could be completely reversed by the infusion of a small-molecule peptide, PM1.
PM1, an inhibitor of a mutated, dysfunctional protein, TAR DNA-binding protein 43 (TDP-43), could alleviate mitochondrial dysfunction and neuronal loss, and could significantly improve motor and cognitive function in previously impaired mice.
Wang is troubled by the fact that PM1 is not a viable drug in humans and that he cannot yet lend a hand to the troubled father.
Wang's team published a study in the January 2017 issue of Molecular Therapy that is seen as confirming the relevance of this neurotoxic pathway, according to an editorial by Eloise Hudry, PhD, of the Alzheimer's Disease Research Unit at Harvard Medical School.
In the Nature Medicine paper, Wang and his colleagues described the accumulation of TDP-43 in the neuronal mitochondria of mice with ALS and FTD. Mutations associated with both diseases were found to be linked to TDP-43 localization within the mitochondria.
This crucial discovery points to a common cause of both neurological diseases such as dementia and motor neuron diseases such as ALS and Parkinson disease. Wang's studies link TDP-43 toxicity directly to mitochondrial bioenergetics and suggest that the targeting of TDP-43 may provide a promising therapeutic approach in the treatment of these apparently disparate diseases.
Wang and his colleagues had shown that the symptoms of ALS in mice could be completely reversed by the infusion of a small-molecule peptide, PM1. "The result astonished everyone in my lab," said Wang. "Even mice with severe motor and cognitive impairment showed a rapid improvement in disease symptoms following the infusion of the peptide, PM1. Previously demented mice were able to learn mazes again and those with severe motor impairment were soon able to walk normally. It seemed to be miraculous. We were stunned."
Wang is searching the FDA library of 700 approved orphan drugs in order to quickly find a drug that can safely reproduce the effects of PM1, which is not viable in humans.
Wang has begun to develop small proteins that prevent TDP-43 from reaching mitochondria in human nerve cells, and has a patent pending for the therapeutic molecule used in the study.
[This researcher, Wang knows how to reverse ALS, and has PATENTED the CURE - and is withholding it.
PM1 is a small-molecule peptide. This article appeared in my search for galantamine and motor neuron disease.]
sciencedaily.com/releases/2...
There is a recognized syndrome called ALS/Parkinson/Dementia Complex, that is alleged to be specific to the Western Pacific.
Following World War II, extremely high rates of a neurodegenerative disease with features of amyotrophic lateral sclerosis, dementia, and Parkinson disease were described in the Western Pacific islands of Guam, the Kii peninsula of Japan, and West Papua, Indonesia.
The prevailing explanation was the cycad hypothesis; that suggests ALS-PDC is caused by eating friut bats, who have a toxin BMAA in their bodies from eating cycad seeds. BMAA is not very neurotoxic, as determined by primate studies, where BMAA was administered in huge doses for 12 weeks, but there was no evidence of delayed or progressive neuro- degeneration.
"The scientific community has been very receptive to the BMAA hypothesis; more than ever, the onus is now on its proponents to provide compelling and credible data." MW Duncan and AM Marini sciencemag.org
Although the definitive etiology is still unknown, the cause of ALS-PDC is most likely a combination of environmental agents coupled with genetic susceptibility.
ALS/PDC has revealed multiple proteinopathies including tauopathy, α-synucleinopathy and TDP-43 proteinopathy (Mimuro et al., 2017)
Oxidative stress (OS) and nitrative stress (NS) are involved in many neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), and ALS (Jesberger and Richardson, 1991; de la Monte et al., 2000; Giasson et al., 2002; Kikuchi et al., 2002; Nunomura et al., 2004; Imaizumi et al., 2012).
The view that ‘degenerative’ neurological conditions such as amyotrophic sclerosis (ALS), Parkinson's disease and Alzheimer's dementia may be caused by environmental toxins has been strengthened by a recent report by Spencer et al. in Science
Cycads contain neurotoxic and genotoxic principles, notably cycasin and methylazoxymethanol (MAM), the latter sharing chemical relations with nitrosamines, which are derived from nitrates and nitrites in preserved meats and fertilizers, and also used in the rubber and leather industries. This review includes new data that influence understanding of the neurobiological actions of cycad and related genotoxins and the putative mechanisms by which they might trigger neurodegenerative disease.
Like all plant materials, the cycad seed is a complex mixture of chemicals, one of which (cycasin) is the principal subject of this paper. We hypothesize that the aglycone of cycasin, the potent genotoxin methylazoxymethanol (MAM), persistently perturbs cell signaling in the young adult brain because post-mitotic nerve cells are unable to repair MAM-induced DNA damage. We have solid evidence to support this conclusion for the developing rodent brain, which MAM readily disrupts, and the fingerprints of a comparable mode of action in the central nervous system of the young adult. If we are correct, MAM represents the first recognized agent with neurotoxic properties that produces a long latency, progressive, neurodegenerative disease, where the interval between agent exposure and onset of neurological decline spans years or decades. We also present evidence that MAM perturbs cell-signaling pathways in the brain that are similar to those activated in mitotically-competent (cycling) epithelial cells that mutate and proliferate to form malignant tumors.
This leads us to propose the possibility that cellular malignancy and progressive neurodegeneration are two sides of the same coin, the outcome depending on whether the genotoxin acts on a cycling or non-cycling cell, respectively.
Since this idea deviates markedly from current understanding and has significant consequences for disease prevention and treatment, we hope our work will stimulate research on this question to prove or disprove our assertion.
ncbi.nlm.nih.gov/pmc/articl...
Cycasin is a cyanogen compound, a toxic glucoside. Plant chemicals with toxic potential can be divided into those containing nitrogen and those lacking this element.
Non-protein amino acids are synthesized in many plant families. Several disrupt the nervous system, others damage the liver, kidney and other organs. Some mimic the action of glutamate, the principle excitatory neurotransmitter in the human central nervous system. Some of these amino acids chealate metals.
Glyphosate
cell.com/trends/neuroscienc...
medlink.com/article/als-lik...
frontiersin.org/articles/10...
[My mom had PD and I have ALS. I theorise these neurological disorders are related and share biological causes for injury and degeneration.]
L-Serine prevents protein from misfolding.
Aluminum, PD, other neurological disorders. AL in Vaccines.
A Bit Off Topic, FMT In A Single Case Report, Stopped ALS Progression And Improved Symptoms
