Recent research in amyotrophic lateral sclerosis (ALS) includes findings involving the CRMP4, FUS and TDP43 genes.
A study conducted in France and Sweden has identified an association between a rare variant in the gene for the collapsing response mediator protein 4 (CRMP4) protein and ALS.
Philippe Corcia at the Université François-Rabelais de Tours (France) and colleagues analyzed the CRMP4 gene in 468 French people with ALS and 183 Swedish study participants with the disease, and compared the results with those derived from French and Swedish control groups (people without ALS).
An association between the CRMP4 gene variant and ALS was found in the French participants, but the investigators could not confirm an association in the Swedish participants. They noted that the study was not large enough to detect an effect in the Swedish group. Alternatively, it's possible that ALS risk associated with the variant is specific to particular populations.
The team published its findings online May 28, 2013, in Human Mutation. To read the full report, for a fee, see: A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS.
A research team based in the United Kingdom, New Zealand and Slovenia has shed light on the role of mutated FUS protein in ALS. Mutations in the fused in sarcoma (FUS) gene are a known cause of the disease.
Christopher Shaw at King’s College London (United Kingdom), and colleagues, confirmed in cell culture studies that ALS-linked FUS mutations disrupt a nuclear localization signal, which causes mutated FUS protein to improperly localize in the main compartment of the cell — the cytoplasm— instead of in the cell nucleus. There, in the presence of a cell-damaging phenomenon called oxidative stress, the mutated protein forms into clumps called inclusions.
Importantly, the team showed that normal FUS protein appears to leave its proper location in the cell nucleus and bind to mutant FUS protein in the cytoplasm, where it helps form inclusions. The investigators say this is a possible mechanism that could explain loss of the normal nuclear function of FUS in ALS.
Understanding the underlying mechanisms that drive ALS disease processes can provide important clues that will help inform the search for therapies.
The team published its findings online March 7, 2013, in Human Molecular Genetics. To read the full report, for free, see: ALS Mutant FUS Disrupts Nuclear Localization and Sequesters Wild-Type FUS Within Cytoplasmic Stress Granules.
Flawed (mutated) TDP43 protein in motor neurons— arising from mutations in the TDP43 gene — is a known cause of ALS. Now, a research team based at King's College London (United Kingdom) has shed light on the role of TDP43 protein in other cell types.
In studies conducted in a fruit fly model of ALS, Frank Hirth and colleagues demonstrated that normal levels of TDP43 protein in both muscle cells and glial cells appear to be essential. Too little or too much protein caused signs and symptoms in the flies that are characteristic of human ALS and frontotemporal lobar degeneration (FTLD).
In muscle cells, researchers found that:
In glial cells:
Both lower- and higher-than-normal levels of TDP43 altered the production and stability of two glutamate transporter proteins, EAAT1 and EAAT2, which help clear away the neurotransmitter glutamate from the area around nerve cells. (Inefficient glutamate clearance has been identified as a possible contributor to ALS.)
The team published its findings online May 31, 2013, in Human Molecular Genetics. To read the full report, at no charge, see: Drosophila TDP43 Dysfunction in Glia and Muscle Cells Cause Cytological and Behavioral Phenotypes that Characterize ALS and FTLD.