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Mutant SOD1, a cause of ALS, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies

A deficiency of the survival of motor neuron (SMN) protein causes SMA and is also reported to be an exacerbating factor in the development of ALS. However, pathways linking the two diseases have yet to be defined and it is not clear precisely how the pathology of ALS is aggravated by reduced SMN or whether mutant proteins underlying familial forms of ALS interfere with SMN-related biochemical pathways to exacerbate the neurodegenerative process.

 

In this study, we show that mutant superoxide dismutase-1 (SOD1), a cause of familial ALS, profoundly alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear ‘gems’ by disrupting the recruitment of the protein to Cajal bodies. Overexpressing the SMN protein in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, most likely in a cell-autonomous manner, and significantly mitigates the loss of motor neurons in the spinal cord and in culture dishes. In the mice, the onset of the neuromuscular phenotype is delayed and motor function enhanced, suggestive of a therapeutic benefit for ALS patients treated with agents that augment the SMN protein. Nevertheless, this finding is tempered by an inability to prolong survival, a limitation most likely imposed by the inexorable denervation that characterizes ALS and eventually disrupts the neuromuscular synapses even in the presence of increased SMN.

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ALS Science
Scientific articles on ALS
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Mice with Lou Gehrig's disease not quite what the doctors ordered

TDP-43 Model mice seem to die of intestinal blockage rather than paralysis. It seems like cientists are still figuring out if the cause is the same, but the symptoms are different.

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Mutant SOD1, a cause of ALS, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies

SMA is caused by a deficiency of the survival of motor neuron (SMN) protein. This is also reported to be an exacerbating factor in the development of ALS.

They show that: 

Mutant SOD1 alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear ‘gems’ by disrupting the recruitment of the protein to Cajal bodies. Overexpressing SMN in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, and significantly mitigates the loss of motor neurons in the spinal cord. 

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Donna Ann's comment, May 6, 2013 2:28 PM
I have familial ALS and only 53 years old.
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Anti-SOD1 Immunization Delays Onset, Increases Lifespan in ALS Mice - The ALS Association

Most if not all SOD1 mutations cause the dimerization interface of SOD1 to be exposed. Some think that exposure of this interface causes lumping of SOD1. Having an antibody bind to this surface clears it for removal. So they made a similar peptide as the exposed surface and developed antibodies to it in mice. This delayed the onset and increased the lifespan of ALS-SOD1 mice

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Oligodendroglia metabolically support axons and contribute to neurodegeneration

Oligodendroglia provide lactate to neurons via protein MCT1. The lactate is vital to the neuron's survival. MCT1 is found in only oligodendroglia in the brain. MCT1 is found to be reduces in ALS patients. 

 

My questions: Do we know of MCT1 mutants in ALS patients? MCT1 seems to have no structure yet. Have the FoldIt guys tried getting a putative structure?

 

Need to explore this more. Thoughts/suggestions welcome

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Marijuana May Extend Life Expectancy Of Lou Gehrig’s Disease Patients, Study Says | NORML Blog, Marijuana Law Reform

The authors claim that an ideal drug regimen for ALS is  one including glutamate antagonists, antioxidants, a centrally acting anti-inflammatory agent, microglial cell modulators (TNF-α inhibitors), an antiapoptotic agent, 1 or more neurotrophic growth factors, and a mitochondrial function-enhancing agent. Preclinical data indicates that cannabis appears to have activity in all of those areas (antioxidative, anti-inflammatory, and neuroprotective effects).

 

In the G93A-SOD1 ALS mouse, cannabis has translated to prolonged neuronal cell survival, delayed onset, and slower disease progression. Cannabis also has properties applicable to symptom management of ALS, including analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. Hence the authors argue for clinical trials with cannabis with the potential objectives of slowing ALS progression, extending life expectancy and substantially reducing the overall burden of the disease.

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AAEM Releases Recommendations for EMF and RF Exposures

ALS patients would likely benefit from avoidance of EMF (electromagnetic frequency) and RF (radiofrequency)

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Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease

Objectives: To quantify the overall contribution of mutations in the currently known ALS genes in a large cohort of sporadic patients (480 SALS and 48 FALS) and to make genotype–phenotype correlations.

 

Results:

* Mutations in 53 patients, with a cumulative frequency of 11%. 7 novel mutations.

* The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%).

* Mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival.

* However, by separately evaluating genotype–phenotype correlation in single genes, clinical differences were observed among different genes.

  ** Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group.

  ** A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations.

  ** Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations.

  ** Mutations were detected in 43.7% of patients with FALS.

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Neuronal phagocytosis by inflammatory macrophages in ALS spinal cord: inhibition of inflammation by resolvin D1

* In post-mortem ALS spinal cords, ~20%
motor neurons, including caspase–negative and caspase-positive neurons, were ingested by IL-6- and TNF-α-positive macrophages.

* In ALS macrophages, in vitro aggregated SOD1 stimulated expression of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, through activation of COX-2 and caspase-1.

* The lipid mediator resolvin D1 (RvD1) inhibited IL-6 and TNF-α production in ALS macrophages 1,100 times more than its parent molecule docosahexaenoic acid.

* ALS peripheral blood mononuclear cells (PBMCs) showed increased transcription of inflammatory cytokines and chemokines at baseline and after stimulation by aggregated wt SOD-1, and these cytokines were down regulated by RvD1.
* Thus the neurons are impacted by macrophages expressing inflammatory cytokines. RvD1 inhibits in macrophages and PBMCs cytokine transcription but does not inhibit their production in PBMCs.

* Resolvins offer a new approach to ALS inflammation suppressing.

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Neurons ravaged by infectious mutant sod

Neurons ravaged by infectious mutant sod | ALS Science | Scoop.it

Lots of support for the prion theory - suggestions that misfolded SOD1 may be inducing even normal SOD1 to misfold. 

 

Questions that pop up in my mind:

* SOD1 has a very interesting electrostatic field around it which has been well studied over decades by biophysicists. The electrostatic field around the protein, due to its unique shape, focuses along certain directions. This enables substrates to approach it faster than brownian motion could ever acheive. This is possible because the focused electrostatic field lines cause its substrate to almost travel in a 2D random walk instead of a 3D random walk to arrive at the active site. Has anyone does a similar study around the structure of mutant SOD1?

* Is there something unique about the electrostatic field and its strength that forces normal SOD1 to misfold itself, when in the presence of misfolded mutant SOD1?

 

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TDP-43 Identified from a Genome Wide RNAi Screen for SOD1 Regulators

Main conclusions:

* TDP-43 and a bunch of other genes regulate SOD1 levels

* This may have an effect on disease pathogenesis

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Rodent models of TDP-43: Recent Advances (Review Article)

To begin to unravel how mutations in TDP-43 cause dysfunction and death of motor neurons, investigators have used both gain- and loss-of-function studies in rodent model systems. Here, they summarize major findings from the initial sets of TDP-43 transgenic and knockout rodent models, identify their limitations, and point to future directions toward clarification of disease mechanism(s) and testing of therapeutic strategies that ultimately may lead to novel therapy for MND/ALS.

http://t.co/zB0Mdrmn...

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Frontotemporal lobar degeneration with TDP-43 proteinopathy and chromosome 9p repeat expansion in C9ORF72: clinicopathologic correlation

Mutations in C9ORF72 resulting in expanded hexanucleotide repeats were recently reported to be the underlying genetic abnormality in chromosome 9p-linked FTLD with TDP-43 proteinopathy (FTLD-TDP), ALS, and FTLD-MND. Several subsequent publications described the neuropathology as being similar to that of FTLD-TDP and ALS without C9ORF72 mutations, except that cases with mutations have p62 and ubiquitin positive, TDP-43 negative inclusions in cerebellum, hippocampus, neocortex, and basal ganglia. The identity of this protein is as yet unknown, and its significance is unclear. To potentially uncover the significance of these inclusions, we compared the clinical, pathologic and genetic characteristics in cases with C9ORF72 mutations to those without.

 

Conclusions:

* Confirmed the apparent specificity of p62 positive, TDP-43 negative inclusions to cases with C9ORF72 mutations. In hippocampus, these inclusions correlated with hippocampal atrophy. No additional correlations were uncovered.

* This is the first report to show that although most cases with C9ORF72 mutations were TDP type B, some of the pathologic characteristics in these cases were more similar to TDP types A and C than to type B cases. These include greater cortical and hippocampal atrophy, greater ventricular dilatation, more neuronal loss and gliosis in temporal lobe and striatum, and TDP-43 positive fine neuritic profiles in the hippocampus, implying that the C9ORF72 mutation modifies the pathologic phenotype of FTLD-TDP type B.

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Cytokinetics Announces Publication of Phase II Evidence of Effect ... - MarketWatch (press release)

Cytokinetics, Incorporated announced today the publication of its Phase II Evidence of Effect (EoE) clinical study of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS). The results published online in the journal Amyotrophic Lateral Sclerosis demonstrated that single oral doses of 250 mg and 500 mg of CK-2017357 appeared safe and well-tolerated in patients with ALS that were studied. Measures of muscle endurance also appeared to be improved in a dose-related fashion in patients who received CK-2017357. In addition, patients who received CK-2017357, and their investigators, perceived a global benefit on treatment. 

 

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Newly discovered biomarker for Lou Gehrig's disease could lead to new therapy

* Big discovery: Monocytes develop a chemical signature targeting them to the spinal cord in ALS patients. In SOD1 mutant mice, these signatures develop before the detection of disease. So the hope is that checking for this biomarker could be a valid way to detect the onset of disease. Also that checking for this level could be a way to verify presence of disease

* Hypothesis: If increased monocyte levels are causatory to the disease, or play a major causal role in the symptoms, then, suppressing their production could be a way to treat ALS. Some preliminary evidence that this may work, observed in lab animals. This may be tested in human trials later.

 

My thoughts:

* ALS is a set of symptoms which may be proven in the future, to be caused by multiple causes. We need to test for these monocyte signatures in all known causes (multiple mutations, singly and possibly in combination)

* The human trial patients also need to be tested for the various mutations (or perhaps the patients should be sequenced). This can help detect if the cure works well only on certain detectable subsets of the disease.

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New Gene Mutations Linked To ALS And Nerve Cell Growth Dysfunction

Summary: Profilin (PFN1) mutations were found in many cases of familial ALS. PFN1 mutations stunt axon growth in lab-grown neurons and mice. Neural profilin accumulates in clumps in neural cells, together with TDP-43. Original paper published in Nature online

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ALS-Associated Ataxin 2 PolyQ Expansions Enhance Stress-Induced Caspase 3 Activation and Increase TDP-43 Pathological Modifications.

Intermediate Length polyQ expansions in Ataxin 2 do a stress-induced activation of Caspases including Caspase 3 which is upstream of TDP-43 cleavage and phosphorylation. ALS patients neurons accumulate cytoplasmic inclusions containing phosphorylated and truncated forms of TDP-43. So perhaps could Caspase 3 inhibitors work for ALS?

 

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Smoking, Alcohol Consumption, and the Risk of Amyotrophic Lateral

Study claims smoking may increase risk of ALS, whereas alcohol consumption may reduce risk.

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Jerusalem - Potentially Groundbreaking ALS Research Benefits ...

Bone marrow cells inserted into the spinal cord seem to be showing great results in one patient in a trial by Brainstorm Cell Therapeutics for ALS. I would love to see more positive results emerge.

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Donna Ann's comment, May 6, 2013 2:10 PM
I would love to be a guinea pig for you.
Donna Ann's curator insight, May 6, 2013 2:31 PM

I wish someone would give me a chance to try this before its too late.

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Orthodox Jewish Rabbi first ALS patient cured by new Israeli drug

---->> interesting: Orthodox Jewish Rabbi first ALS patient cured by new Israeli drug - http://t.co/sW8tlyai <--- Lou Gehrig's disease...
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Donna Ann's comment, May 6, 2013 2:15 PM
I am so ready to try this new drug. PLEASE HELP ME!
Donna Ann's curator insight, May 6, 2013 2:39 PM

Does anyone know about this?

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Asparaginyl endopeptidase cleaves TDP-43 in brain

* TDP-43fragments (∼35 and 32 kDa) predicted to be generated by AEP cleavage at N291 and N306 observed in post-mortem FTLD brain tissue and cultured human cells over-expressing TDP-43.

* AEP can directly cleave TDP-43 at seven sites, including N291 and N306.

* TDP-43 is cleaved by AEP in brain.

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UBQLN2/ubiquilin 2 mutation and pathology in familial ALS

Conclusions:

* Novel missense mutation c.1460C>T (T487I) id'd in 2 unrelated FALS patients with no FTLD. Absent in controls and public databases. T487 is otherwise a highly conserved residue.

* Immunostaining of spinal cord from a patient with T487I Ubiquilin2 showed colocalization of ubiquilin2 with ubiquitin in all neuronal inclusions examined

* Also observed: frequent colocalization with TDP-43 and FUS

 

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Alzheimer's and other dementias linked to post-traumatic stress disorder

Prions or misfolded proteins are suggested as the basis for a lot of CND conditions. 

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Abnormal Protein Expression and Modification in the Spinal Cord with ALS

The authors used proteomics to explore the underlying mechanisms of ALS, and to find out the biomarker for early diagnosis and therapies.

 

Objective: To investigate the difference of protein expression and modification in different area of the nervous system. To address the pathophysiological mechanisms underlying ALS development.

 

Results:

* No significant difference of protein expression except spinal cord. These proteins are modified with different charges.

* The most significant difference is GFAP, which is up-regulated in spinal cord of ALS. Also some others are different in protein expression, such as: NFL, Vimentin and so on. NFL is decreased, Vementin is up-regulated. In addition, some of them were degraded into fragments.

* By using the antibody against common acetylated protein, we find protein acetylation is different in ALS and NON-ALS. Using LC-MS/MS, we first identified three acetylated proteins: Tublin, GFAP and UBS3A.

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Using a zebrafish model of MND to accelerate the development of treatments

A zebrafish model of Motor Neuron Disease (MND), which replicates many of the features of the human disease, will be used by Professor Pamela Shaw and Dr Tennore Ramesh of the MND Association, to study some of the fundamental biochemical processes underpinning the disease and to screen 2,000 drugs for protective effects. The study aims to validate this new model as an accurate and inexpensive means of large-scale screening for protective compounds, in order to accelerate the development of treatments for patients.

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Mutant SOD1, a cause of ALS, disrupts the recruitment of SMN, the spinal muscular atrophy protein to nuclear Cajal bodies

A deficiency of the survival of motor neuron (SMN) protein causes SMA and is also reported to be an exacerbating factor in the development of ALS. However, pathways linking the two diseases have yet to be defined and it is not clear precisely how the pathology of ALS is aggravated by reduced SMN or whether mutant proteins underlying familial forms of ALS interfere with SMN-related biochemical pathways to exacerbate the neurodegenerative process.

 

In this study, we show that mutant superoxide dismutase-1 (SOD1), a cause of familial ALS, profoundly alters the sub-cellular localization of the SMN protein, preventing the formation of nuclear ‘gems’ by disrupting the recruitment of the protein to Cajal bodies. Overexpressing the SMN protein in mutant SOD1 mice, a model of familial ALS, alleviates this phenomenon, most likely in a cell-autonomous manner, and significantly mitigates the loss of motor neurons in the spinal cord and in culture dishes. In the mice, the onset of the neuromuscular phenotype is delayed and motor function enhanced, suggestive of a therapeutic benefit for ALS patients treated with agents that augment the SMN protein. Nevertheless, this finding is tempered by an inability to prolong survival, a limitation most likely imposed by the inexorable denervation that characterizes ALS and eventually disrupts the neuromuscular synapses even in the presence of increased SMN.

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