Transcriptional activation in a mouse model indicated Cullin3 (CUL3) may be a viable therapeutic target for symptoms of autism spectrum disorder (ASD). These findings were published in Nature Communications.
Cul3 model mice were assessed for behavior, underwent staining, whole-proteome analysis, and in vitro transcriptional activation using CRISPR/Cas.
The ASD model mice expressed half the Cul3 protein as control group mice. These mice exhibited increased hind limb clasping (P <.0001), swaying distance (P =.0004), stance distance (P =.03), and social sniffing time (P =.002) and decreased daily latencies (P =.001), coordination (P =.021), and social novelty index (P =.01) as compared with control group mice.
Mice that had a deletion of Cul3 later in life by means of daily tamoxifen injections did not behave differently than control group mice except for reduced motor performance during the accelerating RotaRod test.
BAF chromatin remodeling complex subunit BCL11B (Ctip2) and cut-like homeobox 1 (Cux1) staining revealed the ASD mouse model had laminar thinning among both newborn (P <.01; P =.04) and adult (P =.07; P <.01) mice, respectively. The laminar thinning was coupled with an increase in apoptotic cells in the developing cortex.
During in vitro assays, neural progenitor cells had abnormal cell motility, traveling shorter distances (P =.002) at a reduced speed (P =.0004) in the ASD model compared with control group mice.
The ASD model was associated with deregulated protein expression (146 up- and 94 down-regulated). These genes were involved with DNA-directed RNA polymerase II core complex and proteasome core complex and were linked with the central nervous system and forebrain development as well as cell migration regulation, cytoskeleton organization, cell-cell adhesion, and apoptosis.
Using the CRISPR/Cas system, the investigators increased expression of Cul3 in the ASD model. The mice with transcriptional activation had a rescue of neural cell migration defects, exhibiting the same speed and distance as control group mice.
It remains unclear to what extent these findings may be transferable to patients with ASD.
The study authors concluded that mice with decreased Cul3 expression had behavioral changes and depleted neural cell migration. After transcriptional activation of Cul3, the neural cell phenotypes were restored, indicating this protein may be a viable target for ASD therapeutics.
Morandell J, Schwarz LA, Basilico B, et al. Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development. Nat Commun. Published online May 24, 2021. doi:10.1038/s41467-021-23123-x
This article originally appeared on Psychiatry Advisor