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 & 5 others Hatem El-Shanti, Heather C. Mefford, Gemma L. Carvill, J. Robert Manak, Alexander G. Bassuk

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Article numbere80737
JournalPLoS One
Volume8
Issue number12
DOIs
Publication statusPublished - 3 Dec 2013

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Yeast
Genes
Neurology
Gene Library
Neurons
Neurotransmitter Agents
Brain
Proteins
mutation
Cells
Mutation
epilepsy
Synaptic Vesicles
Peptides
Epilepsy
Yeasts
neurons
yeasts
missense mutation
Aptitude

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Paemka, L., Mahajan, V. B., Skeie, J. M., Sowers, L. P., Ehaideb, S. N., Gonzalez-Alegre, P., ... Bassuk, A. G. (2013). PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. PLoS One, 8(12), [e80737]. https://doi.org/10.1371/journal.pone.0080737

PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. / Paemka, Lily; Mahajan, Vinit B.; Skeie, Jessica M.; Sowers, Levi P.; Ehaideb, Salleh N.; Gonzalez-Alegre, Pedro; Sasaoka, Toshikuni; Tao, Hirotaka; Miyagi, Asuka; Ueno, Naoto; Takao, Keizo; Miyakawa, Tsuyoshi; Wu, Shu; Darbro, Benjamin W.; Ferguson, Polly J.; Pieper, Andrew A.; Britt, Jeremiah K.; Wemmie, John A.; Rudd, Danielle S.; Wassink, Thomas; El-Shanti, Hatem; Mefford, Heather C.; Carvill, Gemma L.; Robert Manak, J.; Bassuk, Alexander G.

In: PLoS One, Vol. 8, No. 12, e80737, 03.12.2013.

Research output: Contribution to journalArticle

Paemka, L, Mahajan, VB, Skeie, JM, Sowers, LP, Ehaideb, SN, Gonzalez-Alegre, P, Sasaoka, T, Tao, H, Miyagi, A, Ueno, N, Takao, K, Miyakawa, T, Wu, S, Darbro, BW, Ferguson, PJ, Pieper, AA, Britt, JK, Wemmie, JA, Rudd, DS, Wassink, T, El-Shanti, H, Mefford, HC, Carvill, GL, Robert Manak, J & Bassuk, AG 2013, 'PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders', PLoS One, vol. 8, no. 12, e80737. https://doi.org/10.1371/journal.pone.0080737
Paemka L, Mahajan VB, Skeie JM, Sowers LP, Ehaideb SN, Gonzalez-Alegre P et al. PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. PLoS One. 2013 Dec 3;8(12). e80737. https://doi.org/10.1371/journal.pone.0080737
Paemka, Lily ; Mahajan, Vinit B. ; Skeie, Jessica M. ; Sowers, Levi P. ; Ehaideb, Salleh N. ; Gonzalez-Alegre, Pedro ; Sasaoka, Toshikuni ; Tao, Hirotaka ; Miyagi, Asuka ; Ueno, Naoto ; Takao, Keizo ; Miyakawa, Tsuyoshi ; Wu, Shu ; Darbro, Benjamin W. ; Ferguson, Polly J. ; Pieper, Andrew A. ; Britt, Jeremiah K. ; Wemmie, John A. ; Rudd, Danielle S. ; Wassink, Thomas ; El-Shanti, Hatem ; Mefford, Heather C. ; Carvill, Gemma L. ; Robert Manak, J. ; Bassuk, Alexander G. / PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. In: PLoS One. 2013 ; Vol. 8, No. 12.
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