title: Intrathecal infusion of BMAA induces selective motor neuron damage and astrogliosis in the ventral horn of the spinal cord.
abstract: The neurotoxin beta-N-methylamino-l-alanine (BMAA) was first identified as a "toxin of interest" in regard to the amyotrophic lateral sclerosis-Parkinsonism Dementia Complex of Guam (ALS/PDC); studies in recent years highlighting widespread environmental sources of BMAA exposure and providing new clues to toxic mechanisms have suggested possible relevance to sporadic ALS as well. However, despite clear evidence of uptake into tissues and a range of toxic effects in cells and animals, an animal model in which BMAA induces a neurodegenerative picture resembling ALS is lacking, possibly in part reflecting limited understanding of critical factors pertaining to its absorption, biodistribution and metabolism. To bypass some of these issues and ensure delivery to a key site of disease pathology, we examined effects of prolonged (30day) intrathecal infusion in wild type (WT) rats, and rats harboring the familial ALS associated G93A SOD1 mutation, over an age range (80±2 to 110±2days) during which the G93A rats are developing disease pathology yet remain asymptomatic. The BMAA exposures induced changes that in many ways resemble those seen in the G93A rats, with degenerative changes in ventral horn motor neurons (MNs) with relatively little dorsal horn pathology, marked ventral horn astrogliosis and increased 3-nitrotyrosine labeling in and surrounding MNs, a loss of labeling for the astrocytic glutamate transporter, GLT-1, surrounding MNs, and mild accumulation and aggregation of TDP-43 in the cytosol of some injured and degenerating MNs. Thus, prolonged intrathecal infusion of BMAA can reproduce a picture in spinal cord incorporating many of the pathological hallmarks of diverse forms of human ALS, including substantial restriction of overt pathological changes to the ventral horn, consistent with the possibility that environmental BMAA exposure could be a risk factor and/or contributor to some human disease.
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Hong Z
authors.initials: HZ
authors.lastname: Yin
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Cheng-I
authors.initials: CI
authors.lastname: Hsu
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Allan
authors.initials: A
authors.lastname: Acab
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Tao
authors.affiliation: Department of Neurology, University of CA, Irvine, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Chiang
authors.affiliation: Department of Neurology, University of CA, Irvine, USA; Department of Anatomy & Neurobiology, University of CA, Irvine, USA. Electronic address: jweiss@uci.edu.
authors.forename: John H
authors.initials: JH
authors.lastname: Weiss
mesh_terms: D000599:Amino Acids, Diamino / Q000633:toxicity*; D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced* / Q000150:complications / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D000087522:Cyanobacteria Toxins; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein; D005911:Gliosis / Q000139:chemically induced* / Q000235:genetics; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051381:Rats; D055647:Rats, Transgenic; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D004268:DNA-Binding Proteins; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; C001824:beta-N-methylamino-L-alanine; C002744:3-nitrotyrosine; D014443:Tyrosine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase