title: PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders.
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.
authors: 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.
authors: Lily
authors: L
authors: Paemka
authors: Vinit B
authors: VB
authors: Mahajan
authors: Jessica M
authors: JM
authors: Skeie
authors: Levi P
authors: LP
authors: Sowers
authors: Salleh N
authors: SN
authors: Ehaideb
authors: Pedro
authors: P
authors: Gonzalez-Alegre
authors: Toshikuni
authors: T
authors: Sasaoka
authors: Hirotaka
authors: H
authors: Tao
authors: Asuka
authors: A
authors: Miyagi
authors: Naoto
authors: N
authors: Ueno
authors: Keizo
authors: K
authors: Takao
authors: Tsuyoshi
authors: T
authors: Miyakawa
authors: Shu
authors: S
authors: Wu
authors: Benjamin W
authors: BW
authors: Darbro
authors: Polly J
authors: PJ
authors: Ferguson
authors: Andrew A
authors: AA
authors: Pieper
authors: Jeremiah K
authors: JK
authors: Britt
authors: John A
authors: JA
authors: Wemmie
authors: Danielle S
authors: DS
authors: Rudd
authors: Thomas
authors: T
authors: Wassink
authors: Hatem
authors: H
authors: El-Shanti
authors: Heather C
authors: HC
authors: Mefford
authors: Gemma L
authors: GL
authors: Carvill
authors: J Robert
authors: JR
authors: Manak
authors: Alexander G
authors: AG
authors: Bassuk
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal; D002659:Child Development Disorders, Pervasive / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D051381:Rats; D016704:Synapsins / Q000235:genetics / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C515173:PRICKLE1 protein, human; C524253:Prickle1 protein, mouse; D016704:Synapsins; D025521:Tumor Suppressor Proteins