C05 SAPAP3 scaffolding protein as a regulator of mitochondrial function in huntington’s disease

Background Huntington’s disease (HD) is a brain disorder characterized by motor and cognitive impairment and early psychiatric disturbances, including obsessive-compulsive disorder (OCD). HD is caused by expansion of CAG repeats at the HTT gene, resulting in expression of mutant huntingtin (mHTT), largely affecting cortico-striatal synapses that are enriched in N-methyl-D-aspartate (NMDA) receptors. Former studies demonstrated that the postsynaptic scaffold protein SAPAP3, mainly located in striatum, is an important player in OCD. Unpublished data indicate that SAPAP3 interacts with several mitochondrial proteins. Hence, striatal dysfunction linked to early mitochondrial deregulation may involve changes in SAPAP3, potentially contributing to early HD symptomatology. Aims Investigate whether altered SAPAP3 protein levels affect striatal function in HD models by focusing on mitochondrial dysfunction as a hallmark of the disease. Methods Determine SAPAP3 protein levels in mitochondria isolated from pre-symptomatic (3 m.o.) and symptomatic (6, 10-12 m.o.) YAC128 transgenic vs WT mice, primary striatal/cortical cultures from YAC128 vs WT mice and STHdhQ111/Q111 vs STHdhQ7/Q7 cells. Study the influence of modulating SAPAP3 levels on mitochondrial function and dynamics in HD cells. Results We showed reduced SAPAP3 total/mitochondrial levels in symptomatic YAC128 mice, mature primary neurons from YAC128 mice and STHdhQ111/Q111 cells, compared to respective controls. In YAC128 striatal and cortical neurons, decreased SAPAP3 levels were pronounced at distal neurites. Colocalization between SAPAP3 and both PSD-95 and GluN2B were affected in YAC128 mouse striatal neurites. Of relevance, silencing SAPAP3 impaired mitochondrial dynamics and function, whereas SAPAP3 overexpression ameliorated these mitochondrial phenotypes in HD cells. Conclusion Our data suggest that SAPAP3 levels impact on mitochondrial function, being a potential neuroprotective target in HD.