TY - JOUR
T1 - PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders
AU - Paemka, Lily
AU - Mahajan, Vinit B.
AU - Skeie, Jessica M.
AU - Sowers, Levi P.
AU - Ehaideb, Salleh N.
AU - Gonzalez-Alegre, Pedro
AU - Sasaoka, Toshikuni
AU - Tao, Hirotaka
AU - Miyagi, Asuka
AU - Ueno, Naoto
AU - Takao, Keizo
AU - Miyakawa, Tsuyoshi
AU - Wu, Shu
AU - Darbro, Benjamin W.
AU - Ferguson, Polly J.
AU - Pieper, Andrew A.
AU - Britt, Jeremiah K.
AU - Wemmie, John A.
AU - Rudd, Danielle S.
AU - Wassink, Thomas
AU - El-Shanti, Hatem
AU - Mefford, Heather C.
AU - Carvill, Gemma L.
AU - Robert Manak, J.
AU - Bassuk, Alexander G.
PY - 2013/12/3
Y1 - 2013/12/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84891789190&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84891789190&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0080737
DO - 10.1371/journal.pone.0080737
M3 - Article
C2 - 24312498
AN - SCOPUS:84891789190
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 12
M1 - e80737
ER -