- Awarded: 2011
- Award Type: Research
- Award #: 206655
The genes implicated in autism thus far support the hypothesis that impaired neuronal connectivity may underlie autism pathogenesis. They also suggest that an imbalance between excitatory and inhibitory synapses — the junctions between neurons — during development may play a role in the disorder. Further knowledge of the protein and pathway interactions for the implicated genes is needed for a better understanding of the underlying pathogenic mechanisms of autism.
Peter Howley and his colleagues at Harvard Medical School generated a human cell line, SH-SY5Y, that can give rise to neuronal cells in which specific protein expression can be induced. Using this cell line, the researchers developed a database of protein-protein interactions that may be physiologically relevant to autism. Because several genes linked to autism encode membrane-associated proteins, they are adapting the system further to enhance the extraction of membrane-associated cellular proteins.
Using this database, Howley’s group is defining the cellular ‘interactomes’ of a number of proteins encoded by autism-associated genes. Initial studies with the three different isoforms of UBE3A, a protein that is encoded within chromosome 15q13 and is believed to be linked to autism, have established that UBE3A is associated with a number of different protein complexes within the cell. These include the proteasome, a cellular structure that degrades unneeded or damaged proteins, and a large protein complex that includes HERC2, NEURL4 and MAPK6.