Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice

Serenella Anzilotti; Valeria Valente; Paola Brancaccio; Cristina Franco; Antonella Casamassa; Giovanna Lombardi; Alessandra Palazzi; Andrea Conte; Simona Paladino; Lorella Maria Teresa Canzoniero; Lucio Annunziato; Giovanna Maria Pierantoni; Giuseppe Pignataro

doi:10.1016/j.biopha.2023.115503

Chronic exposure to l-BMAA cyanotoxin induces cytoplasmic TDP-43 accumulation and glial activation, reproducing an amyotrophic lateral sclerosis-like phenotype in mice

Biomed Pharmacother. 2023 Nov:167:115503. doi: 10.1016/j.biopha.2023.115503. Epub 2023 Sep 18.

Affiliations

¹ Department of Science and Technology, University of Sannio, 82100 Benevento, Italy.
² Department of Molecular Medicine and Medical Biotechnology, School of Medicine, "Federico II" University of Naples, Italy.
³ Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Italy.
⁴ IRCCS SYNLAB SDN S.p.A., 80143 Naples, Italy.
⁵ Department of Molecular Medicine and Medical Biotechnology, School of Medicine, "Federico II" University of Naples, Italy. Electronic address: gmpieran@unina.it.
⁶ Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, "Federico II" University of Naples, Italy. Electronic address: giuseppe.pignataro@unina.it.

PMID: 37729728
DOI: 10.1016/j.biopha.2023.115503

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a progressive and often fatal neurodegenerative disease characterized by the loss of Motor Neurons (MNs) in spinal cord, motor cortex and brainstem. Despite significant efforts in the field, the exact pathogenetic mechanisms underlying both familial and sporadic forms of ALS have not been fully elucidated, and the therapeutic possibilities are still very limited. Here we investigate the molecular mechanisms of neurodegeneration induced by chronic exposure to the environmental cyanotoxin L-BMAA, which causes a form of ALS/Parkinson's disease (PD) in several populations consuming food and/or water containing high amounts of this compound.

Methods: In this effort, mice were chronically exposed to L-BMAA and analyzed at different time points to evaluate cellular and molecular alterations and behavioral deficits, performing MTT assay, immunoblot, immunofluorescence and immunohistochemistry analysis, and behavioral tests.

Results: We found that cyanotoxin L-BMAA determines apoptotic cell death and a marked astrogliosis in spinal cord and motor cortex, and induces neurotoxicity by favoring TDP-43 cytoplasmic accumulation.

Conclusions: Overall, our results characterize a new versatile neurotoxic animal model of ALS that may be useful for the identification of new druggable targets to develop innovative therapeutic strategies for this disease.

Keywords: Amyotrophic Lateral Sclerosis; Behavioral tests; Cyanotoxin; Mice; Neurodegeneration; l-BMAA.