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/ )

Automated summary

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that usually occurs around the age of 60 and has a fatal outcome within 2-5 years of diagnosis. Mouse models based on single gene mutations do not fully replicate ALS pathological features. Environmental factors, such as B-N-methylamino-L-alanine (BMAA), have been linked to increased ALS risk. A two-hit mouse model combining a low expression of a dominant familial ALS mutation and chronic low-dose BMAA exposure was developed, showing a motor phenotype not present in either lesion alone. Analysis confirmed trace levels of free BMAA in the brain and elevated levels in the liver, which were associated with dysregulation of the unfolded protein response pathway. These findings represent initial progress towards a combined genetic and environmental ALS mouse model.