Study Links Loss Of APC Gene with Autistic Behaviors and Cognitive Impairments

Michele Jacob, Ph.D. Professor of Neuroscience Sackler School of Graduate Biomedical Sciences Tufts Interview with
Michele Jacob, Ph.D.
Professor of Neuroscience
Sackler School of Graduate Biomedical Sciences
Tufts University

MedicalResearch: What are the main findings of the study?

Dr. Jacob: Autistic-like behaviors and cognitive impairments associate with loss of the Adenomatous Polyposis Coli (APC) gene.  We deleted APC chiefly from excitatory neurons in the mouse developing forebrain; the mice exhibited changes in synapse maturation and density, reduced social interest, increased repetitive behaviors, and learning deficits.  In addition, we found  molecular changes that define a novel role for APC in linking to and regulating the levels of particular proteins that function in synaptic adhesion complexes and signaling pathways that are required for normal learning and memory consolidation.

MedicalResearch: Were any of the findings unexpected?

Dr. Jacob: Yes. One of the signaling molecules altered by APC loss is presenilin1.  Presenilin gene mutations are the leading cause of familial Alzheimer‘s disease. The role of presenilin in neurodevelopmental brain disorders is not well defined.

In addition, we found excessive levels of Wnt responsive gene expression caused by APC loss.  This change is also predicted for spontaneous mutations in another gene, CHD8, recently identified as a high confidence risk factor for sporadic autism. Thus, our findings are likely relevant to autism and intellectual disabilities caused by other human gene mutations, not only APC.

MedicalResearch: What should clinicians and patients take away from your report?

Dr. Jacob: We are gaining new insights into molecular changes in the developing brain of mouse models that display cognitive and autistic-like disabilities. Identifying key pathways that are deregulated is critical for defining new targets and developing new and effective therapeutic strategies.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Jacob: To utilize diverse genetic mutant and inflammation mouse models that display autistic-like behaviors to elucidate the critical molecular perturbations and relevant brain regions.  Defining convergent changes is essential to design specific therapeutic approaches to ameliorate the disabilities.


Adenomatous polyposis coli protein deletion leads to cognitive and autism-like disabilities
J L Mohn, J Alexander, A Pirone, C D Palka, S-Y Lee, L Mebane, P G Haydon and M H Jacob
Molecular Psychiatry , (17 June 2014) | doi:10.1038/mp.2014.61




Last Updated on June 19, 2014 by Marie Benz MD FAAD