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Published on: October 6, 2017
Aberrant DJ-1 expression underlies L-type calcium channel hypoactivity in dendrites in tuberous sclerosis complex and
Farr Niere1,2, Ayse Uneri1, Colin J McArdle1
1Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157.
Abstract:
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.
Insights
Parkinsonism-associated deglycase (DJ-1) disrupts L-type voltage-gated calcium channel (L-VGCC) activity in neurological diseases like Alzheimer's and Tuberous Sclerosis. This DJ-1 mechanism offers a potential therapeutic target for mTORpathies.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- L-type voltage-gated calcium channels (L-VGCC) are crucial for neuronal function and implicated in neurological diseases.
- The molecular mechanisms regulating L-VGCC density and localization in neurodegenerative disorders remain largely unknown.
- Overactive mammalian target of rapamycin complex 1 (mTORC1) signaling, or mTORpathies, are linked to neurological and psychiatric conditions.
Purpose of the Study:
- To investigate conserved molecular mechanisms of L-VGCC dysfunction in neurodegenerative disorders.
- To explore the role of RNA-binding protein Parkinsonism-associated deglycase (DJ-1) in regulating L-VGCC activity.
- To identify potential therapeutic targets for mTORpathies by examining DJ-1's impact on L-VGCC in Alzheimer's disease (AD) and Tuberous Sclerosis Complex (TSC) models.
Main Methods:
- Utilized preclinical models of Tuberous Sclerosis Complex (TSC) and Alzheimer's disease (AD).
- Assessed the expression and function of DJ-1 and L-VGCC subunits (CaV1.2 and α2δ2) in disease models.
- Investigated DJ-1's binding to CaV1.2 and α2δ2 mRNA and its effect on protein translation in dendrites.
Main Results:
- Increased DJ-1 expression was observed in disease models with overactive mTORC1 signaling.
- DJ-1 directly binds to CaV1.2 and α2δ2 mRNA, repressing their translation specifically in disease states.
- DJ-1-mediated repression of CaV1.2/α2δ2 protein synthesis in dendrites leads to deficits in dendritic L-VGCC calcium activity in AD and TSC models.
Conclusions:
- DJ-1 plays a critical role in regulating L-VGCC activity by controlling the translation of key channel subunits in dendrites.
- DJ-1-mediated disruption of L-VGCC is a conserved mechanism in distinct mTORpathies, including AD and TSC.
- Targeting the DJ-1-regulated L-VGCC pathway presents a novel therapeutic strategy for clinical mTORpathies.
