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Revealing the Mechanisms of Acute and Chronic Cyanotoxic Mixture-induced Neurotoxicity

Award Number: R01ES038200
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/08/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Revealing the Mechanisms of Acute and Chronic Cyanotoxic Mixture-induced Neurotoxicity - Project Summary Amyotrophic Lateral Sclerosis (ALS) is a progressive, fatal motor neuron disease that also frequently compromises sensory function. Although some genetic associations have been established, 90% of ALS cases are sporadic. Several environmental factors have been proposed as contributing factors, with cyanotoxin exposure a leading hypothesis. -N-methylamino-L-alanine (BMAA) is a neurotoxin produced by cyanobacteria that is biomagnified in food sources. BMAA has been linked to ALS-like disease since the 1940s and is hypothesized to exert its effects through neuronal excitotoxicity. Several cyanotoxins co-occur with BMAA in the environment, including the highly prevalent microcystin-LR (MCLR), which has also been linked with neurodegeneration. Yet the key question of whether and how these co-occurring toxins interact to cause increased toxicity when encountered together is unknown. This project leverages the zebrafish model, which is a powerful system for investigating the development and function of behavioral circuits, and modeling human disease. Our preliminary data reveal that exposure to BMAA and MCLR during the first 6 days of development does not alter general larval locomotion. But the toxins do interact to increase acoustic startle responsiveness. This early-life exposure causes long-term sensorimotor dysfunction, as adult fish remain hyperresponsive 2 years later. In Aim 1 we will define the nature of the interaction between BMAA and MCLR as well as the developmental windows when neural circuits are sensitive to BMAA/MCLR exposure with a battery of behavioral assays. Our unbiased proteomic analysis shows that BMAA/MCLR disrupts several pathways associated with excitotoxicity and neurodegeneration, including a 5.7-fold increase in the ALS-linked TDP-43. Furthermore, TDP- 43 mutant larvae are hyporesponsive to acoustic stimuli, consistent with a causal role in cyanotoxin-mediated sensorimotor toxicity. In Aim 3 we will determine which of the top altered pathways drive sensorimotor toxicity using genetic approaches to target a list of six candidate proteins. To then determine if BMAA and/or MCLR interact with known ALS-associated genes, we will test whether sensorimotor dysfunction in SOD1, FUS, or C9orf72 mutants is worsened by cyanotoxin exposure. Finally, using immunohistochemical brain-wide activity mapping we found widespread increases in activity in BMAA/MCLR-exposed larvae. We used targeted calcium imaging to verify that the mixture increases excitability of spinal motor neurons and excitatory hindbrain spiral fiber neurons. In Aim 3 we will define the specific brain regions in which developmental BMAA/MCLR exposure alters the balance of excitation and inhibition with whole-brain lightsheet imaging of transgenic larvae. We will validate these findings with in vivo calcium imaging of identified neurons in toxin-exposed larvae. Overall, the results of this work will establish a molecular program that links cyanotoxic mixture exposure, neural circuit dysfunction, and life-long sensorimotor defects. Furthermore, these aims will lay a foundation for defining the mechanisms by which environmental and genetic factors may interact to cause to human sensorimotor disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $454,477 )
2026	2026	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Environmental Health	000	1	9/8/2026	NEW	$454,477
														Subtotal = $454,477

Grand Total All Awards = $454,477

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Revealing the Mechanisms of Acute and Chronic Cyanotoxic Mixture-induced Neurotoxicity

Award Number: R01ES038200

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/08/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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