ALS

Amyotrophic Lateral Sclerosis (ALS) is strongly associated with oxidative stress.  Nrf2 activators decrease the oxidative stress.  People who have tried Nrf2 Activators have experienced significant improvement from ALS symptoms.  Recent scientific studies have proven that Nrf2 activation helps ALS and may be a good therapy for it.  Following the reviews are current research articles.

Amanda:  This girl was diagnosed with Amyotrophic Lateral Sclerosis (ALS), which progressed within her first year to her needing to use a cane, then a year later she needed a wheelchair, then almost a year later she became totally dependent, with very little movement of her limbs or head.  Her shoulders were stiff and her hands were clenched.  Her parents started giving her Protandim, and 4 days later they noticed significant changes.  Her contracted shoulder could now be lifted without causing her pain, her stiff hands could be relaxed so they could be cleaned, her very faint head movements for "yes" and "no" became more distinct, her facial movements became good enough to mouth some alphabet sounds, and she indicated that she now feels different in a positive way on the inside.  See the video of her on https://www.youtube.com/watch?v=vSIWsfr6bIM.



RESEARCH ARTICLE (pubmed.gov):

Mol Cell Biol. 2015 Jul 15;35(14):2385-99. doi: 10.1128/MCB.00087-15. Epub 2015 May 4.
RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1.
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulated in vitro in motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

PMID: 25939382 [PubMed - in process]
[INTERPRETATION:  RBM45 prevents NRF2 from being activated, thus preventing the body's antioxidants from working to protect the body's nervous system against oxidative stress (cell damage from free radicals).  If Nrf2 were to be activated, it would probably be an important factor in prevention or treatment of ALS.]


RESEARCH ARTICLE (from pubmed.gov): 

PLoS One. 2015 Mar 30;10(3):e0117190. doi: 10.1371/journal.pone.0117190. eCollection 2015.
DJ-1 knockout augments disease severity and shortens survival in a mouse model of ALS.
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson's disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN-1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS.

PMID: 25822630 [PubMed - in process] PMCID: PMC4379040 Free PMC Article
[INTERPRETATION:  ALS is strongly tied to oxidative stress (cell destruction by free radicals).  The Nrf2 mechanism regulates the body's antioxidant response to reduce oxidative stress.  DJ-1 stops the Nrf2 mechanism from working properly, thus accelerating ALS.  Better activation of Nrf2 may be a great therapy for ALS.]