NEUROBIOLOGY SEMINAR SERIES

Peter Penzes, Ph.D.

Professor of Physiology and Psychiatry and Behavioral Sciences,
Director, Center for Autism and Neurodevelopment,
Northwestern University, Feinberg School of Medicine

“Mechanistic substrates of synaptic dysfunction in

neurodevelopmental disorders: focus on 16p11.2 duplication”
Abstract: Research in my laboratory focuses on the molecular and cellular substrates of neurodevelopmental disorders, in-
cluding autism, schizophrenia, bipolar disease, and epilepsy as well as neurodegenerative disorders, such as Alzheimer's dis-
ease. Although with different clinical presentations, these disorders one of their cellular substrates, synapse dysfunction. The
16p11.2 microduplication is a rare form of chromosomal rearrangement that confers risk of multiple neuropsychiatric condi-
tions including, schizophrenia, autism spectrum disorder, bipolar disorder and Rolandic epilepsy. The 16p11.2 chromosomal
region contains 27 protein-coding genes, however, the mechanism by which altered gene dosage in this region increases disease
risk is still incompletely understood. To uncover novel disease-relevant pathways, we undertook a quantitative proteomic pro-
filing of cortical membrane fractions from the 16p11.2 microduplication mouse model (dp/+). We discovered a large set of both
upregulated and downregulated proteins, including proteins within and outside the duplicated 16p11.2 region, suggesting a
widespread proteomic dysregulation. Bioinformatic analysis identified that upregulated and downregulated proteins clustered
into distinct biological processes and were enriched for unique sets of neuropsychiatric risk factors. Candidate proteins from
this screen were studied in cultured neurons with the 16p11.2 duplication using live imaging, immunocytochemistry and bio-
chemical techniques. Finally, we show that the dp/+ mouse model has behavioral phenotypes consistent with its neuropsychiat-
ric and proteomic profile, indicating that systems biology approaches may be able to predict mechanisms and phenotypes in
other disease models. Our work demonstrates that the 16p11.2 microduplication leads to proteomic and behavioural alterations,
which improves our understanding of neuropsychiatric disease mechanisms, and our ability to design rational therapeutics for
affected patients.

NEUROBIOLOGY SEMINAR
Monday, January 14, 2019
12:00 PM- 1:00 PM
Hosted By Bruce Herring
Hedco Neuroscience Auditorium/HNB 100
University Park Campus
3641 Watt Way, Los Angeles, CA 90089
Tel. 213-740-9176
https://dornsife.usc.edu/bisc/neurobiology/