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 similar to 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 ,B-N-methylamino-L-alanine (BMAA) is an environmental toxin linked with an increased risk of devel-oping ALS. BMAA, along with cycasin, are hypothesized to be the cause of the Guam-AL S 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 environ-mental insult.(c) 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )