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.
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
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
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.
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.
* 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.
* 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.
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?
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.
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.
* 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.
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.
* 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.
* 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.
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
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?
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.
* 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.
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.
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.