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

F J Arnold; M Burns; Y Chiu; J Carvalho; A D Nguyen; P C Ralph; A R La Spada; C L Bennett

doi:10.1016/j.neurobiolaging.2023.02.010

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

Neurobiol Aging. 2023 Jun:126:44-57. doi: 10.1016/j.neurobiolaging.2023.02.010. Epub 2023 Feb 23.

Authors

F J Arnold¹, M Burns², Y Chiu³, J Carvalho⁴, A D Nguyen⁴, P C Ralph⁴, A R La Spada⁵, C L Bennett⁶

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
² Department of Neurology, Duke University School of Medicine, Durham, NC, USA; Departments of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA.
³ Molecular Education, Technology and Research Innovation Center, North Carolina State University, Raleigh, NC, USA.
⁴ Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
⁵ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC, USA; Departments of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, USA; Department of Neurology, University of California, Irvine, Irvine, CA, USA; Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA; UCI Center for Neurotherapeutics, University of California, Irvine, Irvine, CA, USA. Electronic address: [email protected].
⁶ Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA, USA; Department of Neurology, Duke University School of Medicine, Durham, NC, USA. Electronic address: [email protected].

PMID: 36931113
DOI: 10.1016/j.neurobiolaging.2023.02.010

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 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.

Keywords: ALS; BMAA; Guam; Mass-spectrometry; Parkinsonism; TDP-43.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acids, Diamino* / genetics
Amino Acids, Diamino* / toxicity
Amyotrophic Lateral Sclerosis* / chemically induced
Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / metabolism
Animals
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Disease Models, Animal
Mice
Motor Neurons / pathology
Neurodegenerative Diseases* / complications
Phenotype

Substances

Amino Acids, Diamino
DNA-Binding Proteins
TDP-43 protein, mouse

Grants and funding

R35 NS122140/NS/NINDS NIH HHS/United States