PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders

Lily Paemka; Vinit B Mahajan; Jessica M Skeie; Levi P Sowers; Salleh N Ehaideb; Pedro Gonzalez-Alegre; Toshikuni Sasaoka; Hirotaka Tao; Asuka Miyagi; Naoto Ueno; Keizo Takao; Tsuyoshi Miyakawa; Shu Wu; Benjamin W Darbro; Polly J Ferguson; Andrew A Pieper; Jeremiah K Britt; John A Wemmie; Danielle S Rudd; Thomas Wassink; Hatem El-Shanti; Heather C Mefford; Gemma L Carvill; J Robert Manak; Alexander G Bassuk

doi:10.1371/journal.pone.0080737

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PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders

Journal article

Open access

Peer reviewed

PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders

Lily Paemka, Vinit B Mahajan, Jessica M Skeie, Levi P Sowers, Salleh N Ehaideb, Pedro Gonzalez-Alegre, Toshikuni Sasaoka, Hirotaka Tao, Asuka Miyagi, Naoto Ueno, …

PloS one, Vol.8(12), pp.e80737-e80737

2013

DOI: 10.1371/journal.pone.0080737

PMCID: PMC3849077

PMID: 24312498

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Abstract

The frequent comorbidity of Autism Spectrum Disorders (ASDs) with epilepsy suggests a shared underlying genetic susceptibility; several genes, when mutated, can contribute to both disorders. Recently, PRICKLE1 missense mutations were found to segregate with ASD. However, the mechanism by which mutations in this gene might contribute to ASD is unknown. To elucidate the role of PRICKLE1 in ASDs, we carried out studies in Prickle1(+/-) mice and Drosophila, yeast, and neuronal cell lines. We show that mice with Prickle1 mutations exhibit ASD-like behaviors. To find proteins that interact with PRICKLE1 in the central nervous system, we performed a yeast two-hybrid screen with a human brain cDNA library and isolated a peptide with homology to SYNAPSIN I (SYN1), a protein involved in synaptogenesis, synaptic vesicle formation, and regulation of neurotransmitter release. Endogenous Prickle1 and Syn1 co-localize in neurons and physically interact via the SYN1 region mutated in ASD and epilepsy. Finally, a mutation in PRICKLE1 disrupts its ability to increase the size of dense-core vesicles in PC12 cells. Taken together, these findings suggest PRICKLE1 mutations contribute to ASD by disrupting the interaction with SYN1 and regulation of synaptic vesicles.

Neurons - pathology

Child Development Disorders, Pervasive - metabolism

Synaptic Vesicles - metabolism

Tumor Suppressor Proteins - metabolism

Humans

Rats

Synaptic Vesicles - pathology

Child Development Disorders, Pervasive - physiopathology

LIM Domain Proteins - metabolism

PC12 Cells

Synapsins - genetics

Synapsins - metabolism

Behavior, Animal

Animals

Child Development Disorders, Pervasive - genetics

Mice, Mutant Strains

Tumor Suppressor Proteins - genetics

Adaptor Proteins, Signal Transducing - genetics

LIM Domain Proteins - genetics

Mice

Neurons - metabolism

Mutation

Adaptor Proteins, Signal Transducing - metabolism

Synaptic Vesicles - genetics

Details

Title: Subtitle: PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders
Creators: Lily Paemka - The University of Iowa, Iowa City, Iowa, United States of America ; Department of Pediatrics, The University of Iowa, Iowa City, Iowa, United States of America ; Interdisciplinary Program in Genetics, The University of Iowa, Iowa City, Iowa, United States of America
Vinit B Mahajan
Jessica M Skeie
Levi P Sowers
Salleh N Ehaideb
Pedro Gonzalez-Alegre
Toshikuni Sasaoka
Hirotaka Tao
Asuka Miyagi
Naoto Ueno
Keizo Takao
Tsuyoshi Miyakawa
Shu Wu
Benjamin W Darbro
Polly J Ferguson
Andrew A Pieper
Jeremiah K Britt
John A Wemmie
Danielle S Rudd
Thomas Wassink
Hatem El-Shanti
Heather C Mefford
Gemma L Carvill
J Robert Manak
Alexander G Bassuk
Resource Type: Journal article
Publication Details: PloS one, Vol.8(12), pp.e80737-e80737
DOI: 10.1371/journal.pone.0080737
PMID: 24312498
PMCID: PMC3849077
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: T32 GM008629 / NIGMS NIH HHS R21 MH100086 / NIMH NIH HHS F32 EY022280 / NEI NIH HHS 1R01 NS064159-01A1 / NINDS NIH HHS K08EY020530 / NEI NIH HHS 1R21MH100086-01 / NIMH NIH HHS R01 EY026682 / NEI NIH HHS K08 EY020530 / NEI NIH HHS
Language: English
Date published: 2013
Academic Unit: Neurology; Psychiatry; Medical Genetics and Genomics; Surgery; Biology; Craniofacial Anomalies Research Center; Rheumatology, Allergy, and Immunology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Radiation Oncology; Neurology (Pediatrics); Neurosurgery; Internal Medicine; Ophthalmology and Visual Sciences
Record Identifier: 9984003957302771

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