Drosophila prickle mutants display comorbid neurological phenotypes and present with autism spectrum disorder-associated phenotypes

Krishna M Nukala; Brady Williquett; Anthony J Lilienthal; Dakota M Thompson; Josephine N Massingham; Shu Hui Lye; Avery Yu; Bridget C Lear; G Gregory Neely; Stanislava Chtarbanova; J Robert Manak

doi:10.1016/j.nbd.2026.107623

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Drosophila prickle mutants display comorbid neurological phenotypes and present with autism spectrum disorder-associated phenotypes

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Drosophila prickle mutants display comorbid neurological phenotypes and present with autism spectrum disorder-associated phenotypes

Krishna M Nukala, Brady Williquett, Anthony J Lilienthal, Dakota M Thompson, Josephine N Massingham, Shu Hui Lye, Avery Yu, Bridget C Lear, G Gregory Neely, Stanislava Chtarbanova, …

Neurobiology of disease, Vol.230, 107623

10/08/2026

DOI: 10.1016/j.nbd.2026.107623

PMID: 42849579

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Abstract

Epilepsy affects approximately 30% of individuals with autism spectrum disorder (ASD). Consistent with these observations, while PRICKLE mutations are primarily linked with epilepsy, there is an enrichment of pathogenic DNA sequence variants in PRICKLE genes carried by individuals with ASD. Nonetheless, a connection between PRICKLE function and ASD warrants further investigation. Here, we show that a seizure-prone Drosophila prickle mutant (prickle-spiny-legs, or pk ) exhibits learning and memory deficits, increased pain sensitivity, both communication and social interaction difficulties, and restrictive repetitive grooming behaviors, all of which are strongly correlated with ASD, while a non-seizure prone prickle mutant (prickle-prickle, or pk ) does not, thereby associating epilepsy and ASD through prickle. Comparing headed versus headless pk mutants, we also show that the excessive grooming requires higher level cognitive processing from the brain. Finally, both pk and pk mutants exhibit circadian rhythm defects, another feature correlated with ASD, as well as distinct yet overlapping neurological anomalies in processes that include innate immune response, oxidative stress response, neuronal cell death, neurodegeneration, motor dysfunction and reduced lifespan, likely reflecting the unique isoform expression patterns observed in the developing CNS. Collectively, this study highlights the broadscale effects of PRICKLE mutations that extend beyond the primary clinical features of epilepsy to include several of the core features of ASD.

Oxidative Stress

Epilepsy

Neuroinflammation

Drosophila

Autism spectrum disorder

Glial innate immune system

Details

Title: Subtitle: Drosophila prickle mutants display comorbid neurological phenotypes and present with autism spectrum disorder-associated phenotypes
Creators: Krishna M Nukala - University of Iowa
Brady Williquett - University of Iowa
Anthony J Lilienthal - University of Iowa
Dakota M Thompson - University of Iowa
Josephine N Massingham - The University of Sydney
Shu Hui Lye - University of Alabama
Avery Yu - University of Iowa
Bridget C Lear - University of Iowa
G Gregory Neely - The University of Sydney
Stanislava Chtarbanova - University of Alabama
J Robert Manak - University of Iowa
Resource Type: Journal article
Publication Details: Neurobiology of disease, Vol.230, 107623
DOI: 10.1016/j.nbd.2026.107623
PMID: 42849579
NLM abbreviation: Neurobiol Dis
ISSN: 1095-953X
eISSN: 1095-953X
Publisher: Elsevier
Grant note: National Institutes of Health: R01NS098590 University of Alabama
Funding This work was supported by National Institutes of Health grant R01NS098590 (JRM, Alexander G. Bassuk) . SC was supported by startup funds from the University of Alabama.
Language: English
Date published: 10/08/2026
Academic Unit: Stead Family Department of Pediatrics; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9985244583302771

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