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ALS Science
Scientific articles on ALS
Curated by Ragu Bharadwaj
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Local lab company offering test for ALS - Worcester Telegram

Local lab company offering test for ALS - Worcester Telegram | ALS Science | Scoop.it
Local lab company offering test for ALSWorcester TelegramThe function of the C9orf72 gene remains unknown. Athena is ... “A single individual does not have much to gain by screening for the C9orf72 mutation.” ...
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Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival

Emerging evidence from clinical studies and transgenic mouse models of ALS suggests that cannabinoids, the bioactive ingredients of marijuana (Cannabis sativa) might have some therapeutic benefit in this disease. However, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the predominant cannabinoid in marijuana, induces mind-altering effects and is partially addictive, compromising its clinical usefulness. We therefore tested whether cannabinol (CBN), a non-psychotropic cannabinoid, influences disease progression and survival in the SOD1 (G93A) mouse model of ALS.

 

Conclusions:

* Cannabinol, a non-psychotropic cannabinoid, significantly delays disease onset in mice by > 2 weeks while survival was not affected, in G93A SOD1 mice.

* Further research is necessary to determine whether non-psychotropic cannabinoids might be useful in ameliorating symptoms in ALS.

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Immune system and inflammation linked to Lou Gehrig's disease

Immune system and inflammation linked to Lou Gehrig's disease | ALS Science | Scoop.it

Conclusions:

* Inflammation initiated by the immune system in ALS can trigger macrophages to also ingest healthy neurons.

* During the inflammation process, motor neurons, whether healthy or not, are marked for clean-up by the macrophages.

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Mutant FUS induces endoplasmic reticulum stress in amyotrophic ...

Mutant FUS induces endoplasmic reticulum stress in amyotrophic ... | ALS Science | Scoop.it

Mutations in the gene encoding fused in sarcoma (FUS) are linked to ALS, but the mechanisms by which these mutants trigger neurodegeneration remain unknown. Endoplasmic reticulum (ER) stress is increasingly recognized as an important and early pathway to motor neuron death in ALS. FUS is normally located in the nucleus but in ALS, FUS redistributes to the cytoplasm and forms inclusions. In this study, we investigated whether FUS induces ER stress in a motor neuron like cell line (NSC-34).

 

Conclusion:

* ER stress is triggered in cells expressing mutant FUS, and this is closely associated with redistribution of mutant FUS to the cytoplasm. Mutant FUS also colocalized with protein disulfide-isomerase (PDI), an important ER chaperone, in NSC-34 cells and PDI was colocalized with FUS inclusions in human ALS lumbar spinal cords, in both sporadic ALS and mutant FUS-linked familial ALS tissues.

* These findings implicate ER stress in the pathophysiology of FUS, and provide evidence for common pathogenic pathways in ALS linked to the ER.

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A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants - Fujisawa - Annals of Neurology - Wiley Online Library

A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants - Fujisawa - Annals of Neurology - Wiley Online Library | ALS Science | Scoop.it

Objective:
Although more than 100 different Cu, Zn superoxide dismutase (SOD1) mutations are identified in ALS patients, it remains controversial whether all of them are disease-causative mutations. Therefore, it is necessary to develop the molecular mechanism-based diagnosis and treatment of ALS caused by SOD1 mutations.

 

Methods:
We previously reported that three pathogenic mutations of SOD1 cause chronic endoplasmic reticulum (ER) stress by inducing the binding of SOD1 to Derlin-1, a component of the ER homeostatic machinery. Here, we systematically analyzed 132 SOD1 mutants and found that most have a constitutively exposed Derlin-1-binding region (DBR) that is occluded in the wild-type protein. To develop the novel molecular mechanism-based antibody that can specifically recognize the aberrant structure of toxic SOD1 mutants, we generated the monoclonal antibody against the DBR.

 

Results:
MS785, a monoclonal antibody generated against the DBR, distinguished most of ALS-causative SOD1 mutants from both wild-type and non-toxic mutants. Moreover, MS785 recognized endogenous SOD1 in B-lymphocytes derived from 14 ALS patients carrying SOD1 mutations but not from 11 healthy controls.

 

Interpretation:
This is the first study to address the common property of all ALS-causative SOD1 mutants. MS785 is the first molecular mechanism-based antibody that was shown to be able to distinguish ALS-linked toxic SOD1 mutants from both wild-type and non-toxic mutants. MS785 may thus become an innovative tool for the diagnosis of ALS. 

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New ALS Research Involves TDP-43, Motor Neurons, Other Findings - The ALS Association

New ALS Research Involves TDP-43, Motor Neurons, Other Findings - The ALS Association | ALS Science | Scoop.it
Reducing expression of TDP-43 increases the level of SOD1. The finding highlights a previously unknown molecular link between two genetic causes of ALS and may lead to a better understanding of disease pathogenesis.
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Mutant superoxide dismutase-1 indistinguishable from wild type causes ALS

A novel c.352C>G (L117V) SOD1 mutation was found in two Syrian ALS-families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, were equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V-patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene.

 

Conclusions:  

* SOD1 mutations that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS.

* L117V SOD1 is one such mutation

* Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.

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Clinical and Pathological Continuum of Multisystem TDP-43

Objective:

To determine the extent of transactivation response DNA-binding protein with a molecular weight of 43 kDa (TDP-43) pathology in the central nervous system of patients with clinically and autopsy-confirmed diagnoses of frontotemporal lobar degeneration with and without motor neuron disease and amyotrophic lateral sclerosis with and without cognitive impairment.

 

Main Outcome: Measure Neuronal and glial TDP-43 pathology.

 

Results:

We found evidence of neuronal and glial TDP-43 pathology in all disease groups throughout the neuraxis, albeit with variations in the frequency, morphology, and distribution of TDP-43 lesions. Moreover, the major clinical manifestations (eg, cognitive impairments, motor neuron signs, extrapyramidal symptoms, neuropsychiatric features) were reflected by the predominant distribution and burden of TDP-43 pathology.

 

Conclusion:

These findings strongly suggest that ALS, FTLD with ALS or motor neuron disease, and FTLD with ubiquitinated inclusions are different manifestations of a multiple-system TDP-43 proteinopathy linked to similar mechanisms of neurodegeneration.

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Amyloid precursor protein (APP) contributes to pathology in the SOD1G93A ALS mouse

In ALS the progressive loss of motor neurons is accompanied by extensive muscle denervation, resulting in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS patients and the SOD1G93A mouse model of familial ALS. We have further characterized this response in SOD1G93A mice and also revealed elevated levels of β-Amyloid (Aβ) peptides in the SOD1G93A spinal cord, which were predominantly localized within motor neurons and their surrounding glial cells. We therefore examined the effect of genetic ablation of APP on disease progression in SOD1G93A mice, which significantly improved multiple disease parameters, including innervation, motor function, muscle contractile characteristics, motor unit and motor neuron survival.

 

Conclusions:

* APP actively contributes to SOD1G93A-mediated pathology. Together with observations from ALS cases, this study indicates that APP may contribute to human ALS pathology.

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The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder | BioPortfolio.com

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to ALS and FTD. Here we describe the frequency, origin and stability of this mutation in ALS+/−FTD from five European cohorts (total n=1347).

 

In a London clinic cohort, the HREM was the most common mutation in familial ALS+/−FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10−8).

 

Conclusion:

HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.

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Does a loss of TDP-43 function cause neurodegeneration?

A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the strikingneurodegenerative phenotypes in numerous TDP-43-overexpression models.

 

Conclusions:

* This review draws attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominantnegative effect on the wild-type TDP-43 allele.

* Furthermore, it discusses how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, and highlights some key questions for testing this hypothesis in the future.

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Interaction of Cisplatin with Human Superoxide Dismutase - Journal of the American Chemical Society (ACS Publications)

Interaction of Cisplatin with Human Superoxide Dismutase - Journal of the American Chemical Society (ACS Publications) | ALS Science | Scoop.it
RT 1960s-era anti-cancer drug points to treatments for Lou Gehrig's disease http://t.co/EogeiKaq [via @J_A_C_S]...
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