Aberrant DJ-1 expression underlies L- type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer's disease

L -type voltage -gated calcium (Ca2+) channels (L-VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown whether molecular mechanisms leading to disrupted L-VGCC across neurodegenerative disorders are conserved. Importantly, L-VGCC integrate synaptic signals to facilitate a plethora of cellular mechanisms; however, mechanisms that regulate L-VGCC channel density and subcellular compartmentalization are understudied. Herein, we report that in disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), deficits in dendritic L-VGCC activity are associated with increased expression of the RNA- binding protein (RBP) Parkinsonism-associated deglycase (DJ -1). DJ -1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and alpha 262, and represses their mRNA translation, only in the disease states, specifically preclinical models of tuberous sclerosis complex (TSC) and Alzheimer's disease (AD). In agreement, DJ- 1- mediated repression of CaV1.2/alpha 262 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L-VGCC calcium activity. Finding of DJ- 1- regulated L-VGCC activity in dendrites in TSC and AD provides a unique signaling pathway that can be targeted in clinical mTORopathies.