- Awarded: 2014
- Award Type: Explorer
- Award #: 326244
A small protein called ubiquitin is added to other proteins to modify their function, causing changes in cellular behavior. Often, the addition of ubiquitin leads to the complete destruction of the tagged protein. This process, called ubiquitination, plays an important role in regulating the abundance of many proteins at neuronal junctions, or synapses, including receptors within the postsynaptic density (a brain region that contains receptors and other proteins that regulate neuronal function).
Naturally occurring mutations that cause loss of function in the CUL3-based E3 ligase gene were identified in two separate next-generation sequencing studies of people with inherited autism1,2. These individuals have one normal allele and one non-functional allele, and therefore have the capacity to make less CUL3, one of the proteins that adds ubiquitin to other proteins.
Genetic studies indicate that SHANK3, which helps assemble a group of proteins to mediate proper function at the postsynaptic density, is a strong autism candidate. Using a mouse strain with reduced CUL3 expression levels in the brain, Jeffrey Singer and his colleagues found that SHANK3 is regulated in the CUL3-mediated pathway. The researchers suggest that CUL3 regulates the abundance of SHANK3 by tagging it with ubiquitin with the help of one of two proteins, KLHL17 and KLHL2. This regulation may be essential for normal assembly of the postsynaptic density. An understanding of how these proteins interact will provide valuable information in understanding autism.
Singer’s team plans to examine the role of the CUL3-mediated pathway in autism-related behaviors in animals expressing low levels of CUL3. They propose that partial or complete loss of CUL3 function in mice may result in behavioral phenotypes similar to autism. The researchers also plan to examine the role of the CUL3-mediated pathway in regulating SHANK3 by determining how KLHL17 or KLHL2 bring CUL3 to the postsynaptic density to ubiquitinate SHANK3, leading to its degradation.