Finding A New Drug Target To Treat Frontotemporal Lobar Degeneration

Professor Haruhisa Inoue (Department of Cell Growth and Differentiation) recently led a team effort to identify α2δ-2 inhibition as a target of frontotemporal lobar degeneration.

Frontotemporal Lobar Degeneration (FTLD) is a neurodegenerative disease affecting the frontal and temporal lobes that regulate higher cognitive brain functions such as personality, behavior, and language. FTLD-tau is characterized by Tau protein misfolding and accumulation and neuronal cell death, and despite valiant efforts by scientists worldwide, no effective treatments for disease modification are currently available.

In a previous study using cortical neurons generated from iPS cells derived from FTLD patients (FTLD neurons), Inoue and his team identified a link between neuronal hyperexcitability caused by dysregulated calcium control and neurodegeneration caused by Tau accumulation.

As such, in this study, they tested a panel of existing anti-epileptic drugs (reduces neuronal excitability) to determine whether they could protect FTLD neurons. Among the tested compounds, gabapentin exhibited neuroprotective effects. In addition, gabapentin treatment of FTLD neurons led to reduced Tau oligomers but no detectable change in total Tau levels, thus suggesting it inhibits Tau protein misfolding. Because gabapentin (a gabapentinoid), is known to bind to and inhibit one of the auxiliary subunits of voltage-gated calcium channels (α2δ), the researchers tested other gabapentinoids in FTLD neurons and observed similar neuroprotection upon treatment.

Furthermore, since there are four α2δ proteins and gabapentinoids inhibit the α2δ-1 and α2δ-2 subtypes, the research team also removed the genes encoding the α2δ-1 and α2δ-2 proteins (CACNA2D1 and CACNA2D2, respectively) together or separately from FTLD neurons to determine which was the main target of gabapentinoids for FTLD-tau. Interestingly, whereas removing CACNA2D1 did not reverse the detrimental effects of neuronal death in FTLD neurons, FTLD neurons without CACNA2D2 (alone or in conjunction with CACNA2D1) showed suppressed neuronal death and reduced accumulation of Tau oligomers.

For a molecular understanding of how α2δ-2 inhibition may protect FTLD neurons against Tau-mediated neurotoxicity, the research team generated cerebral organoids using iPS cells derived from a healthy subject, FTLD patient, or FTLD patient with the CACNA2D2 knockout. The researchers performed single-cell RNA sequencing using the cerebral organoids to identify gene expression profile changes triggered by the FTLD-causing mutations that are rescuable by CACNA2D2 knockout. Notably, they identified changes in the expression of several genes potentially related to FTLD pathology, but further analyses are necessary to clarify their effects.

Drug screening and mechanistic analysis using iPS cells derived from FTLD patients revealed that α2δ2, encoded by the CACNA2D2 gene, is a promising therapeutic target for FTLD-Tau. Existing drugs such as gabapentin, pregabalin, and mirogabalin, which act on α2δ2, have demonstrated potential as therapeutic agents for FTLD. FTLD is a currently incurable neurodegenerative disease that causes profound changes in personality and behavior, as well as dementia. These findings pave the way for the development of a mechanism-based therapy for FTLD. Based on these results, the team is preparing to initiate a clinical trial for patients with FTLD.