Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an average age-of-onset of ∼60 years and is usually fatal within 2-5 years of diagnosis. Mouse models based upon single gene mutations do not recapitulate all ALS pathological features. Environmental insults may also contribute to ALS, and ß-N-methylamino-L-alanine (BMAA) is an environmental toxin linked with an increased risk of developing ALS. BMAA, along with cycasin, are hypothesized to be the cause of the Guam-ALS epicenter of the 1950s. We developed a multihit model based on low expression of a dominant familial ALS TDP-43 mutation (Q331K) and chronic low-dose BMAA exposure. Our two-hit mouse model displayed a motor phenotype absent from either lesion alone. By LC/MS analysis, free BMAA was confirmed at trace levels in brain, and were as high as 405 ng/mL (free) and 208 ng/mL (protein-bound) in liver. Elevated BMAA levels in liver were associated with dysregulation of the unfolded protein response (UPR) pathway. Our data represent initial steps towards an ALS mouse model resulting from combined genetic and environmental insult.

Psychoneurotic profiles in the adult population.

Self-reported psychoneurotic characteristics and aspects of affective status have been examined within the adult population of a market town and the surrounding rural community using a standardized instrument. Features of anxiety in particular are more common amongst females than males, peaking in the third, fourth (phobic avoidance behaviour being also especially evident at this time) and fifth decades of life. Many of the characteristics are also importantly related to age in both sexes and to social class. Some are widespread within the population and probably reflect more enduring personality traits. Others are less common, more age specific (e.g. early adult life, middle age, the menopause in females; the involutional period in males) and are probably more often construed by the individuals concerned and by others as 'illness'. The similarity of the relevant segment of the present profiles to those previously obtained from a suburban population aged 40-65 years is noteworthy. The most likely interpretation is that the measuring instrument is reliable and that the reporting behaviour of psychoneurotic and effective characteristics and morbidity is identical in both populations.