Available online 23 February 2023

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L-BMAA combined with TDP-43−Q331K at low expression causes motor dysfunction

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Chronic 200 PPM dosing in mice induces L-BMAA protein association

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Long-term BMAA exposure analyzed using SIL-BMAA Mass Spectrometry

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Motor Neuron surface area is reduced with L-BMAA and TDP-43−Q331K exposure

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Mice exposed to L-BMAA diets for 16 months duration starting at 2 months

ABSTRACT

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 β-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 multi-hit 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.

Key words

BMAA

TDP-43

ALS

mass-spectrometry

Guam

Parkinsonism

ABBREVIATIONSAmyotrophic lateral sclerosis

ALS

Central Nervous System

CNS

β-N-methylamino-L-alanine

BMAA

L-β-N-oxalyl-α-β-diaminopropionic acid

β-ODAP

Neuromuscular Junction

NMJ

Parkinsonism Dementia Complex

PDC

Availability of data and materials

The data and materials are available from corresponding authors on reasonable request.

© 2023 The Author(s). Published by Elsevier Inc.