The Thierry Latran Foundation is pleased to provide scientific information selected by a group of French neurologist. The Foundation expresses warm thanks to them for their support.

Highlights 21st International Symposium on ALS/MND – ORLANDO 11-13 décembre 2010

Work carried out in collaboration by PF Pradat (Paris), D Devos (Lille), JP Camdessanché (Saint-Etienne), P Corcia (Tours), M Abdelnour Mallet (Paris) et N Guy (Clermond-Ferrand)

The 21st International congress on motor neuron disease in Orlando was rich of very interesting information. Numerous hypothesis that could turn to new therapeutically approach were presented, even if they were not “scoops” strictly speaking. This summary doesn’t pretend to be exhaustive but to present a selection of topics that we consider to be of high interest or innovative.

Role of glial cells

Toxicity induced by mutated SOD 1 protein, responsible of rare inherited forms of ALS in human, lead to dysfunctions in motor neuron but also glial cells. Expression of the mutant protein in those cells would be linked to the disease progression, or even more could induce experimentally a motor neuron disease, as it has been demonstrated in a mouse model. Thus, separate researcher’s teams have tried to identify how expression of mutantSOD1 in glial cells, especially astrocytes, could play a role in modifying disease progression. In a rodent model carrying SOD1 mutated gene, the analysis of RNA and protein synthesis revealed that astrocytes have an abnormal maturation (Yang and al.). They over express Nerve Growth Factor reported as potentially toxic for mature motor neuron while some proteins expression as Monocarboxylatetransporter, involved in carbohydrate (source of energy) metabolism in motor neuron are decreased. (Ferraiuolo and al). Those misregulations would concern more widely other types of glial cells (Lee and al.).
The important role of glial cells in the survival of motor neurons lead to try to develop therapies that target astrocytes or microglia to slow disease progression, including stem cell replacement or gene silencing approaches.

Axon degeneration function

Axonal transport impairment protein contributing to their degeneration has been demonstrated in animal model. In particular a protein normally transported along axons in vesicular structure Nmnat (Nicotinamide mononucleotide adenyltransferase) participates to axon survival. Maintaining an appropriate level of this protein could be a therapeutic target to slow down axon degeneration (Coleman and al.). Structures involved in the synthesis and selection of proteins such as endoplasmic reticulum and the Golgi apparatus could also play an important role. This includes the concept of “endoplasmic reticulum stress.” In cultures of cells and animal models expressing the mutated SOD-1 protein, there are defects of interaction between vesicles from the endoplasmic reticulum and the Golgi apparatus. These anomalies could contribute to the “endoplasmic reticulum stress” leading to the death of the cell and abnormal secretion of growth factors important for the survival of motor neuron such as BDNF (Brain Derived Neurotrophic Factor) (Farg and al.).

ALS and inclusion body myositis: common mechanisms?

Multiple sessions were devoted to new methods of genetic analysis, including pangenomic techniques. They differentiate from conventional techniques designed to search for targeted genetic defects at the level of genes or genomic regions already known. New approaches are able to analyze whole genomes with automated techniques (so-called “high through put sequencing”). These techniques are still in the field of research. They have proven recently their value with the identification of a new gene involved in rare family forms of ALS, using a technique called “exon sequencing” (exon is part of a gene sequences that encode the protein directly). This new gene is the VCP gene for “valsolin-containing protein”. Surprisingly, this gene was known to be responsible for another rare disease associating inclusion body myositis (muscle disease affecting adults), Paget’s disease (bone disease) and frontal cortical disorder. However, in the first descriptions of this entity, motor impairment was not reported to have a muscular origin but a motor neuron disease. It is therefore legitimate to further question the relationships between ALS and inclusion body myositis. Following the same route, the Pitié-Salpêtrière (Paris) team showed a similarity between TDP-43 protein anomalies observed in inclusion and some family forms of ALS. These findings reinforce the potential role of muscle abnormalities in ALS, which, as in inclusion body myositis, could involve inflammatory factors responsive to immunomodulatory treatment.

Role of altered RNA Biology in ALS

Human RNA reproduced the information from DNA in genes for the synthesis of proteins. A session of the Congress was devoted to the role of altered RNA processing in the death of neurons (neurodegeneration) during ALS. One of the arguments comes from the recent identification of ALS- causing mutations in the genes encoding for two proteins TDP-43 (43kDa TARS DNA-binding domain protein) and FUS (Fused in Sarcoma), two RNA/DNA binding proteins. One of the feature in ALS, found in sporadic forms and certain family forms (this is not the case for example of family forms related to mutations in the SOD1 gene) is the accumulation as cytoplasmic aggregates of TDP – 43 in, while normally this protein is mainly nuclear. Different studies on cell cultures or animal models argue for the role of abnormal processing of RNA messenger. TDP-43 RNA binding sites has been identified and it was shown that a loss of function of TDP-43 could be responsible for an abnormal mRNA maturation. (Lagier-Tourenne C and al, San Diego ; Kim SH and al, Madisson ; Freibaum B and al, Memphis ; Xiao S and al, Toronto). Among the RNA that does’nt code for proteins, there are small portions of RNA called “microRNA” able to bind to other part of RNA, modulating the synthesis of proteins. These “micro-RNA” would be less numerous in motor neurons of patients with sporadic ALS compared to control patients. The role of micro-RNA in the pathogenesis remains to clarify even if here also it is suspected to be an abnormal regulation of RNA maturation leading to abnormalities in protein synthesis. (Liou L and al, Washington).

Treatment by G – CSF: pre-clinical data

G – CSF (“granulocyte colony stimulating factor”) is a growth factor that has a set of properties that make it an interesting candidate for the treatment of ALS: it promotes neurogenesis, angiogenesis and has anti-apoptotic and anti-inflammatory effects. Pollari and al. used this treatment in a mouse model of ALS (carrying SOD1 mutation responsible of family forms of the disease). Mice were treated before the start of symptoms. Authors observed a better survival rate for the treated mice with on histological analysis, a better preservation of motor neuron and a decrease in inflammation. Within the limits of course of extrapolations in humans based on animal data, this work however reopen the interest of G – CSF treatment. We remind that a preliminary study in a small series of 39 patients showed good tolerance of the treatment. It had not been observed clinical improvement, but the small number of patients in this study does absolutely not allow concluding on the potential benefit of this treatment.