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Updated: Jun 16, 2025
High-throughput Functional Screening using a Homemade Dual-glow Luciferase Assay
Published on: June 1, 2014
iPSC screening identifies CACNA2D2 as a potential therapeutic target for FTLD-Tau
Keiko Imamura1, Ayako Nagahashi2, Aya Okusa2
1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan; iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan; RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan.
Abstract:
Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disorder that affects the frontal and temporal lobes, which are crucial for regulating personality, behavior, and language. Pathologically, FTLD is characterized by Tau protein accumulation and neuronal death. In our effort to identify disease-modifying treatments, we conducted drug screening using neurons derived from induced pluripotent stem cells (iPSCs) of FTLD-Tau patients. This screening identified gabapentin as an existing drug that suppresses neuronal cell death with suppressed accumulation of Tau oligomers. Treatment with gabapentinoids, including pregabalin and mirogabalin, demonstrated similar neuroprotective effects. These compounds bind to the α2δ subunit of voltage-dependent calcium channels and specifically target the two isoforms α2δ-1 and α2δ-2. To determine which isoform is involved in the neurodegeneration seen in FTLD-Tau, we employed a knockout approach using iPSCs, which revealed that α2δ-2, encoded by CACNA2D2, plays a key role in the degeneration of FTLD-Tau neurons. Moreover, Neural organoids of FTLD-Tau exhibited features indicative of neurodegeneration, and CACNA2D2 knockout reversed a part of the gene expression alterations associated with these neurodegenerative features. These findings suggest that α2δ-2 may be a promising target for disease-modifying therapies in FTLD-Tau.
Insights
Gabapentin and related drugs protect against neuronal death in Frontotemporal Lobar Degeneration (FTLD)-Tau. The α2δ-2 calcium channel subunit is identified as a key factor in FTLD-Tau neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disease impacting personality, behavior, and language due to frontal and temporal lobe damage.
- Pathologically, FTLD involves Tau protein accumulation and neuronal loss.
- Current treatments focus on symptom management, lacking disease-modifying strategies.
Purpose of the Study:
- To identify potential disease-modifying treatments for FTLD-Tau.
- To investigate the role of specific calcium channel isoforms in FTLD-Tau neurodegeneration.
- To explore gabapentinoids as a therapeutic intervention for FTLD-Tau.
Main Methods:
- Drug screening using induced pluripotent stem cell (iPSC)-derived neurons from FTLD-Tau patients.
- Utilizing knockout approaches in iPSCs to assess the function of α2δ-1 and α2δ-2 calcium channel subunits.
- Employing FTLD-Tau neural organoid models to study neurodegenerative features and gene expression changes.
Main Results:
- Gabapentin was identified as a drug that reduces neuronal cell death and Tau oligomer accumulation in FTLD-Tau neurons.
- Gabapentinoids (pregabalin, mirogabalin) showed similar neuroprotective effects.
- Knockout of the α2δ-2 subunit (encoded by CACNA2D2) in iPSCs demonstrated its critical role in FTLD-Tau neuronal degeneration.
- CACNA2D2 knockout partially reversed gene expression alterations in FTLD-Tau neural organoids.
Conclusions:
- The α2δ-2 subunit of voltage-dependent calcium channels is implicated in FTLD-Tau neurodegeneration.
- Gabapentin and its analogs exhibit neuroprotective properties against FTLD-Tau pathology.
- Targeting the α2δ-2 subunit presents a potential therapeutic strategy for developing disease-modifying treatments for FTLD-Tau.
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