ALS Research News (A monthly summary of significant articles about ALS research)
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
This summary includes some of the most recent advances in ALS research. If you would like certain news items featured, or have questions, please contact researchgrants@alsa-national.org
Mitochondrial abnormalities could be the result of axonal transport defects in a familial model of ALS
A group of scientists from the U.K. led by Christopher Miller and Andrew Grierson published a study in Human Molecular Genetics showing that SOD1 mutations known to cause familial ALS in humans reduce the transport of mitochondria, the cell’s energy supply, from the cell body to the axon terminals without affecting their transport back to the soma. This imbalance results in the depletion of mitochondria in axon terminals, which could be one of the earliest pathological features of ALS disease. Back to Top
Mitochondria, axonal transport, mouse models
Reduction of Akt, an anti-apoptotic protein in motor neurons in sporadic and familial ALS patients
A recent study published in Neuropathology and Applied Neurobiology led by Ludo Van den Bosch in Belgium, found that motor neurons of both sporadic and familial ALS patients lack phospho-Akt (protein kinase B), a protein that normally prevents cell death. Interestingly, vascular endothelial growth factor (VEGF), a trophic factor that has previously been shown to increase survival in mouse models expressing mutant SOD1, counteracts the loss of phospho-Akt providing a mechanism by which motor neurons could be protected against cell death. Therapies aimed at increasing the levels of phospho-Akt could be of clinical relevance for ALS. Back to Top
VEGF, anti-apoptotic protein, ALS therapies
Embryonic cell transplantation in the brain: potential for upper motor neuron replacement
Replacement of upper and/or lower motor neurons is a potential therapy for ALS disease. A French group led by Mohamed Jaber published in Nature Neuroscience a study showing that cells extracted from embryonic motor cortex tissue and transplanted into adult mice with damaged motor cortex are capable of re-establishing the cortical circuitry appropriately, in particular with the spinal cord. These findings offer potential for neural cell transplantation to promote cortico-spinal reconstruction in ALS. Back to Top
Stem cell, regenerative therapies
A novel mechanism forEAAT2 in ALS pathology
Researchers led by Piera Pasinelli and Davide Trotti from Thomas Jefferson University in Philadelphia published a recent study in the Journal of Biological Chemistry that provides insight into the role of EAAT2 in a mouse model expressing mutant SOD1. EAAT2 is a glutamate transporter expressed in astrocytes involved in clearing excess glutamate that would injure motor neurons. The investigators have shown previously that mutant SOD1 protein present in some inherited forms of ALS activates an enzyme, caspase 3, which leads to the generation of two fragments. Here they describe alterations to one of the fragments providing novel insight into EAAT2 abnormalities in ALS. Back to Top
EAAT2 pathophysiological mechanism, animal model
Pin1, a novel therapeutic target?
Researchers led by Pant at the National Institute for Neurological Disorders and Stroke in Bethesda published a study in Molecular Biology of the Cell that sheds light on a possible mechanism underlying abnormal accumulation of phosphorylated neurofilament proteins surrounding the cell nucleus in ALS. They show that Pin1, an enzyme that normally regulates the phosphorylation of proteins, associates with phosphorylated neurofilament-H (NFH)...Mimicking in a dish the stress induced by glutamate excitotoxicity on motor neurons, the authors show that Pin1 inhibition reduces the accumulation of phosphorylated neurofilament-H and prevents neuronal death. Inhibition of Pin1 provides a potential therapeutic approach for ALS. Back to Top
Phosphorylated NFH, therapies
New ALS gene targets for ALS treatment?
Published studies have implicated reactive oxygen species in ALS. Several proteins present in the body produce reactive oxygen species as part of their normal function in the cell. NADPH oxidases Nox1 and Nox2 are thought to play an important role in this process. A team led by John Engelhardt at the University of Iowa in Iowa City published a study in the Journal of Clinical Investigation showing that reducing the amount of these proteins significantly extends survival in transgenic mice expressing mutant SOD1. The effect on survival was greater than a similar study using a different strain of mice suggesting that modifier genes may play a role in this pathway. Back to Top
Nox genes, new ALS gene modifiers targets for ALS treatment
Clinical trial of TCH346 does not show benefit for ALS patients
Results from a clinical trial designed to test the effects of TCH346, a drug that blocks apoptosis in motor neurons was reported in Neurology by Miller and collaborators. The results from the trial provide no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS. Back to Top
Anti-apoptotic, clinical trial
Technological advances for reprogramming cells into stem cells
Research reported in Cell Stem Cell by Robert Blelloch and colleagues from University of California in San Francisco shows progress in somatic cell reprogramming to the pluripotent stem cell state that may allow the development of models of ALS disease in a Petri dish. Prior efforts at reprogramming fibroblasts that give rise to the connective tissue such as cartilage relied on genetically engineered fibroblasts to express a gene resistant to drug selection. Here the authors improved the technique so that it does not require drug selection, thus improving the ability to generate pluripotent stem cells from somatic cells. These findings represent a step forward in the development of methods that would allow reverting cells from patients with ALS to a more primitive state enabling their differentiation into motor neurons and glia. Back to Top
Methodology, stem cell clinical application
Insight into the cellular mechanism of VAPB mutation leading to motor neuron degeneration
A study published in Journal of Neuroscience by the Dutch group led by Dirk Jaarsma and Casper Hoogenraad at the Erasmus Medical Center gives insight into how the P56S mutation in the gene-encoding vesicle-associated membrane protein-binding protein B (VAPB), identified recently in a familial form of ALS (ALS8), could lead to motor neuron degeneration. Using a combination of cell biology, immunofluorescence and biochemistry in transgenic mice expressing mutant SOD1 and in tissue from ALS patients, they show that the VAPB mutant protein abundantly expressed in motor neurons forms aggregates, traps endogenous wild-type VAP thus impairing normal VAP function and impairs lipid-binding protein function that could result in abnormal lipid transport and biosynthesis. The combination of these events could explain how the VAPB mutation leads to motor neuron death. Back to Top
VAPB pathophysiological mechanism, sALS, ER
Astrocytes control motor neurons vulnerability to glutamate damage through regulation of GluR2 expression
In a study published in the Proceedings of the National Academy of Sciences, Belgian researchers working with Wim Robberecht propose a novel mechanism by which astrocytes influences the vulnerability of motor neurons to excess glutamate, the neurotransmitter involved in the transmission of information from the brain to the spinal cord. Taking advantage of the differential neuroprotective effect exerted by astrocytes from two different mouse strains, the investigators showed a differential expression of the glutamate AMPA receptor GluR2 in motor neurons in the two strains. Interestingly, he ability of astrocytes to modulate motor neuron levels of GluR2 is abolished in the presence of mutant SOD1 making the motor neurons more vulnerable to glutamate toxicity. This mechanism adds to the importance of astrocytes in maintaining the health of motor neurons. Back to Top
AMPA GluR2 pathophysiological mechanisms, astrocytes
TDP-43 found in the neostriatum of ALS patients
Wabayashi’s group from Hirosaki University in Japan published in Acta Neuropathologica on the presence of TDP-43 proteins in the neostriatum of patients with classical ALS and ALS patients with dementia suggesting the implication of the neostriatum in ALS disease. Back to Top
TDP-43, neostriatum, FTD
A possible link between TDP-43 and progranulin
Leonard Petrucelli and colleagues from the Mayo Clinic College of Medicine in Jacksonville published a study in the Journal of Neuroscience that sheds light on the pathological processes contributing to fronto-temporal dementia (FTD) and ALS. Mutations in the progranulin gene are linked to some inherited forms of FTD. Recently, TDP-43 protein has been shown to be a pathological component of inclusions present in the nerve cells and surrounding cells in some patients with FTD and in ALS patients. In the present study, the investigators show that a decrease in progranulin proteins leads to an increase in caspase-3 degradation pathways and pathological cleavage of TDP-43. Interestingly, reducing the expression of progranulin leads to a redistribution of TDP-43 from its normal location in the nucleus to the cytoplasm. Back to Top
TDP-43 and PRGN
ITPR2: a novel susceptibility factor for ALS.
Researchers led by Van den Berg at the University Medical Center in Utrecht in the Netherlands published a genome-wide association study in Lancet Neurology, and suggest that the inositol 1, 4, 5-triphosphate receptor 2 gene (ITPR2) is a strong candidate for a susceptibility gene associated with sporadic ALS... ITPR2 is involved in glutamate neurotransmission, calcium regulation and apoptosis. Back to Top
