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

Abstract

L-type voltage-dependent Ca2+ channels (L-VDCC) integrate synaptic signals to facilitate a plethora of cellular mechanisms. L-VDCC dysfunction is implicated in several neurological and psychiatric diseases. Despite their importance, signals upstream of L-VDCC activity that regulate their channel density, however, are poorly defined. In disease models with overactive mammalian target of rapamycin complex 1 (mTORC1) signaling (or mTORopathies), including tuberous sclerosis (TS) and Alzheimers disease (AD), we report a novel mechanism downstream of mTORC1 signaling that results in a deficit in dendritic L-VDCC activity. Deficits in L-VDCC activity are associated with increased expression of the mTORC1-regulated RNA-binding protein DJ-1. DJ-1 binds the mRNA coding the auxiliary Ca2+ channel subunit 2{delta}2 responsible for shuttling L-VDCC to the membrane and represses its expression. Moreover, this novel DJ-1/2{delta}2/L-VDCC pathway is disrupted in human AD and preclinical models of AD and TS. Our discovery that DJ-1 directs L-VDCC activity and L-VDCC-associated protein 2{delta}2 at the synapse suggests that DJ-1/2{delta}2/L-VDCC is a common, fundamental pathway disrupted in TS and AD that can be targeted in clinical mTORopathies. Significance StatementMany neurological disorders share symptoms, despite disparity among diseases. Treatments are prescribed based on diagnosis rather than individual symptoms. While only treating symptoms may obscure the disease, mechanism-based drug development allows the two approaches to converge. Hub proteins, those that coordinate the expression of proteins that mediate specific cellular functions, may be dysregulated across a broad range of disorders. Herein, we show that the RNA-binding protein DJ-1 controls the activity of L-type voltage-dependent calcium channels (L-VDCC), via the expression of its auxiliary subunit alpha2delta2 (2{delta}2). Importantly, we demonstrate that this novel DJ-1/2{delta}2/L-VDCC pathway is commonly disrupted among neurological disorders, namely Alzheimers disease (AD) and Tuberous Sclerosis (TS). Collectively, these data rationalize mechanism-based drug therapy to treat disease.