Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and Alzheimer’s disease
Abstract
L-type voltage-gated calcium (Ca 2+ ) 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 Ca 2+ channel subunits Ca V 1.2 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 Ca V 1.2/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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 30, 2023
- Source ID
- 10.1073/pnas.2301534120
Entities
People
- Ayse Uneri
- Cameron Reynoldson
- Chelcie F. Heaney
- Christopher Keene
- Colin J. Mcardle
- Farr Niere
- Hailey X. Egido-Betancourt
- Juan Penaranda
- Kimberly F Raab-Graham
- Luisa P. Cacheaux
- Michael P. Stierer
- Samuel H. Barth
- Sanjeev V. Namjoshi
- Suzanne Craft
- Tao Ma
- William C. Taylor
- Xin Wang
- Zhiyong Deng
Organizations
- Alzheimer's Association
- Congressionally Directed Medical Research Programs
- Division of Biological Infrastructure
- Fraxa Research Foundation
- National Institute of Neurological Disorders and Stroke
- National Institute on Aging
- National Institute on Alcohol Abuse and Alcoholism
- North Carolina Agricultural and Technical State University
- University of Washington
- Wake Forest School of Medicine
- Wake Forest University