PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

Qingqing Wang; Michael J. Moore; Guillaume Adelmant; Jarrod A. Marto; Pamela A. Silver

doi:10.1101/gad.212308.112

PQBP1, a factor linked to intellectual disability, affects alternative splicing associated with neurite outgrowth

¹Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
²Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York 10065, USA;
³Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA;
⁴Blais Proteomics Center,
⁵Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA;
⁶Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts 02115, USA

Abstract

Polyglutamine-binding protein 1 (PQBP1) is a highly conserved protein associated with neurodegenerative disorders. Here, we identify PQBP1 as an alternative messenger RNA (mRNA) splicing (AS) effector capable of influencing splicing of multiple mRNA targets. PQBP1 is associated with many splicing factors, including the key U2 small nuclear ribonucleoprotein (snRNP) component SF3B1 (subunit 1 of the splicing factor 3B [SF3B] protein complex). Loss of functional PQBP1 reduced SF3B1 substrate mRNA association and led to significant changes in AS patterns. Depletion of PQBP1 in primary mouse neurons reduced dendritic outgrowth and altered AS of mRNAs enriched for functions in neuron projection development. Disease-linked PQBP1 mutants were deficient in splicing factor associations and could not complement neurite outgrowth defects. Our results indicate that PQBP1 can affect the AS of multiple mRNAs and indicate specific affected targets whose splice site determination may contribute to the disease phenotype in PQBP1-linked neurological disorders.