- Awarded: 2025
- Award Type: Pilot
- Award #: SFI-AN-AR-Pilot-00009224
Hypoxia-inducible factor (HIF), which consists of a labile HIFa subunit and stable HIFb (ARNT) subunit, is a master transcription factor that activates genes whose products promote adaptation under low oxygen1. Acute HIF pathway activation increases synaptic plasticity, and has beneficial effects on neurological disorders, such as depression or autism spectrum disorders. Conversely, HIF inhibition reduces cognitive function and decreases neuronal survival. How HIF regulates synaptic plasticity and neuronal function is incompletely understood.
Synaptic junctions are modifiable functional units that are essential in information processing in the brain. Neurexin (Nrxn) synaptic proteins are key organizing centers that promote synapse assembly and plasticity. Nrxn is a heparan sulfate (HS) proteoglycan (HSPG) and disruption of Nrxn HS glycation alone is sufficient to decrease synapse development. Mutations in NRXN and its essential HS biosynthetic enzymes, such as EXT1 and EXT3, have been found in human ASD suggesting a shared genetic risk pathway2. The mechanisms that regulate Nrxn HS glycation and how they are altered in ASD remain unclear.
Gregory Wyant has discovered that HIFa increases Neurexin HS glycation. Mechanistically, his lab has identified that HIF controls Deleted in Autism 1 (DIA1), a protein of unknown function previously identified in inherited cases of ASD in consanguineous families, found to be critical in hypoxia induced Neurexin HS glycation3.
The Wyant Lab will determine the molecular function of DIA1 and its role in cellular HS metabolism and synaptic function. To gain mechanistic insight into how HS glycation controls synaptic function, they plan to determine, on a proteome-wide scale, HS-modified proteins and how they are altered in ASD.
Collectively, these studies will provide the initial insight into DIA1 function in ASD and novel insights into HS control of ASD.