Sumoylation of OPHN1 controls spine density and architecture by tuning actin dynamics

Ophn1 gene encodes Oligophrenin-1 (OPHN1), a Rho-GAP protein highly expressed in neurons. In humans, all Ophn1 mutations cause the loss of function of OPHN1 leading to syndromic intellectual disability (ID) characterized by cerebellum abnormalities. In neurons, OPHN1 regulates dendritic spine density and architecture, actin dynamics and AMPA receptor (AMPAR) trafficking. Interestingly, we identified for the first time OPHN1 as a novel target of sumoylation. Sumoylation is a post-translational modification essential to the modulation of several neuronal functions, including neurotransmitter release and synaptic plasticity. Altered sumoylation has been associated with neurological disorders. Here, we combined molecular biology with live imaging and super resolution microscopy to address the role of sumoylation in controlling OPHN1 function in hippocampal neurons. Excitingly, we demonstrated that sumoylation controls the activation state of OPHN1. By this mechanism, sumoylation controls the actin dynamics which in turn impact dendritic spine density and architecture. Furthermore, since the sumoylation site is located close to the novel missense mutation (G412D) identified in ID patients, we explored thrilling hypothesis that compromised sumoylation may lead to synaptic dysfunction associated to the ID phenotype.
Altogether, our results clearly demonstrate that sumoylation is a novel regulatory mechanism tuning OPHN1 activity. Furthermore, since the ID-linked G412D mutation impacts OPHN1 sumoylation and affects spine density and morphology, AMPAR surface expression as well as actin polymerization rate to a similar extent as the non-sumoylatable OPHN1 mutant, our data support the hypothesis that impaired OPHN1 sumoylation may participate to the etiology of ID in patients carrying the G412D mutation.