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  • Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer’s disease
Title: 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 α2δ2, 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/α2δ2 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.  more » « less
Award ID(s):
2200474
PAR ID:
10504201
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publisher / Repository:
National Academy of Sciences
Date Published:
Journal Name:
Proceedings of the National Academy of Sciences
Volume:
120
Issue:
45
ISSN:
0027-8424
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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