Mouse models for examining impacts of BMAA on neurodegeneration
Dr. Gregory Cox, The Jackson Laboratory
ALS is estimated to afflict 30,000 Americans, with 5000 new cases annually. The genetic heterogeneity observed in familial forms of ALS (FALS) and the high proportion of sporadic ALS (SALS) cases suggest that several genetic and environmental factors are necessary for the initiation of motor neuron disease in patients. Dominant SOD1 mutations account for approximately 25% of FALS, though heterogeneity in the age of onset or severity of symptoms can be observed within families. This suggests that modifier genes exist in the population that can, in the right (or wrong) combinations, significantly impact the sensitivity of people to genetic or neurotoxic insults. The nature of genetic insults leading to ALS has advanced with the recent identification of TDP-43 and FUS gene mutations in certain FALS patients, but the identity of potential environmental neurotoxins has been a source of great interest and speculation. Based on the epidemiological studies of patient clusters in isolated communities such as the ALS Parkinsonism dementia complex (ALS-PDC) of the native Chamorro people in Guam, native cycad plants were identified as a source of an environmental toxin. Efforts soon focused on an unusual amino acid, b-methylamino-L-alanine (BMAA), synthesized by cyanobacteria that are found in the cycad roots. Cyanobacteria are present worldwide and exposure to BMAA may be a common trigger for sporadic forms of ALS. We hypothesize that the BMAA molecule can be incorporated at a low level into the proteins of motor neurons and cause them to aggregate and eventually kill the cells. What is so exciting is that this mechanism has the potential to explain the very long latency (time from exposures to illness) and late onset of the disease. Genetic susceptibility to toxins such as BMAA must play a part since not everyone who is exposed develops disease. We are ideally suited to test this hypothesis using our many different inbred strains of normal and sensitized mice at The Jackson Laboratory. We are currently performing pilot studies attempting to generate a model of sporadic ALS by long-term dietary exposure to BMAA. The genetic diversity among our inbred strains should allow the identification of genes that regulate susceptibility and resistance to this potential environmental trigger of neurodegeneration. We are also exposing mice that carry genetic predisposition mutations for neurodegenerative disease (SOD1G93A and TDP43A315T) to dietary BMAA to test the hypothesis that the neurotoxic effects of exposure will accelerate disease and provide a mechanism for gene-environment interactions. Accelerated models of disease will prove useful both for the analysis of disease mechanisms but also for preclinical trials for therapeutic intervention.