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The AAA+ ATPase, Thorase, plays a critical role in controlling synaptic plasticity, learning and memory through regulating the expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR). Here, by sequencing a cohort of schizophrenia patients we identify Thorase rare variants (TRV) that cause defects in glutamatergic signaling through impairment in AMPAR internalization, recycling and function. Internalization of AMPAR is significantly reduced in neurons expressing TRVs, leading to increased surface expression of the AMPAR subunit GluA2 and enhanced synaptic transmission. Furthermore, these defects lead to mouse behavioral deficits in schizophrenia-like models and importantly these impairments are rescued by the competitive AMPAR antagonist, perampanel. These findings suggest that Thorase could be an important mediator of symptoms associated with schizophrenia-like behaviors, and support the FDA approved AMPAR antagonist perampanel as a potential treatment strategy for patients with compromised AMPAR-mediated glutamatergic neurotransmission.

Parkinson's disease (PD) is a common neurodegenerative disorder caused by genetic and environmental factors that results in degeneration of the nigrostriatal dopaminergic pathway in the brain. We analyzed neural cells generated from induced pluripotent stem cells (iPSCs) derived from PD patients and presymptomatic individuals carrying mutations in the PINK1 (PTEN-induced putative kinase 1) and LRRK2 (leucine-rich repeat kinase 2) genes, and compared them to those of healthy control subjects. We measured several aspects of mitochondrial responses in the iPSC-derived neural cells including production of reactive oxygen species, mitochondrial respiration, proton leakage, and intraneuronal movement of mitochondria. Cellular vulnerability associated with mitochondrial dysfunction in iPSC-derived neural cells from familial PD patients and at-risk individuals could be rescued with coenzyme Q(10), rapamycin, or the LRRK2 kinase inhibitor GW5074. Analysis of mitochondrial responses in iPSC-derived neural cells from PD patients carrying different mutations provides insight into convergence of cellular disease mechanisms between different familial forms of PD and highlights the importance of oxidative stress and mitochondrial dysfunction in this neurodegenerative disease.