Aberrant DJ‐1 expression underlies L‐type calcium channel hypoactivity in dendrites in Alzheimer’s disease (AD) and tuberous sclerosis complex (TSC)

Abstract

AbstractBackgroundL‐type voltage‐dependent Ca2+ channels (L‐VGCC) dysfunction is implicated in several neurological and psychiatric diseases. While a popular therapeutic target, it is unknown if molecular mechanisms leading to disrupted L‐VGCC across neurodegenerative disorders is 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.MethodThe following methods were used: bioinformatics; RNA immunoprecipitation; Surface Sensing of Translation–Proximity Ligation Assay (SUnSET‐PLA); calcium imaging, immunocytochemistry; Western blots, dissociated hippocampal neurons and acute hippocampal slices from APP/PS1 mouse mode of AD and Tsc1 conditionally knockout mice; Postmortem human prefrontal cortex tissue.ResultHerein, 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) DJ‐1. DJ‐1 binds the mRNA coding for the alpha and auxiliary Ca2+ channel subunits CaV1.2 and alpha2delta2 (α2δ2), and represses their mRNA translation, only in the disease states, specifically preclinical models of Alzheimer’s disease (AD) and tuberous sclerosis complex (TSC). In agreement, DJ‐1 mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites is exaggerated in mouse models of AD and TSC, resulting in deficits in dendritic L‐VGCC calcium activity. These preclinical findings are recapitulated in the synaptic and dendritic regions of prefrontal cortices of humans diagnosed with AD.ConclusionDiscovery of DJ‐1 regulated L‐VGCC activity in dendrites in TSC and AD provides a new signaling pathway that can be targeted in clinical mTORopathies.