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Published on: May 16, 2019
Filamin A inhibition reduces seizure activity in a mouse model of focal cortical malformations
Longbo Zhang1,2, Tianxiang Huang1,2, Shannon Teaw1
1Departments of Neurosurgery and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8082, USA.
Abstract:
Epilepsy treatments for patients with mechanistic target of rapamycin (mTOR) disorders, such as tuberous sclerosis complex (TSC) or focal cortical dysplasia type II (FCDII), are urgently needed. In these patients, the presence of focal cortical malformations is associated with the occurrence of lifelong epilepsy, leading to severe neurological comorbidities. Here, we show that the expression of the actin cross-linking protein filamin A (FLNA) is increased in resected cortical tissue that is responsible for seizures in patients with FCDII and in mice modeling TSC and FCDII with mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes. Normalizing FLNA expression in these mice through genetic knockdown limited cell misplacement and neuronal dysmorphogenesis, two hallmarks of focal cortical malformations. In addition, Flna knockdown reduced seizure frequency independently of mTOR signaling. Treating mice with a small molecule targeting FLNA, PTI-125, before the onset of seizures alleviated neuronal abnormalities and reduced seizure frequency compared to vehicle-treated mice. In addition, the treatment was also effective when injected after seizure onset in juvenile and adult mice. These data suggest that targeting FLNA with either short hairpin RNAs or the small molecule PTI-125 might be effective in reducing seizures in patients with TSC and FCDII bearing mutations in PI3K-Rheb pathway genes.
Insights
Targeting filamin A (FLNA) offers a new epilepsy treatment strategy for patients with mechanistic target of rapamycin (mTOR) disorders like tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII). Reducing FLNA expression alleviates seizures and neuronal abnormalities.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Epilepsy associated with tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) requires novel treatments.
- These conditions involve focal cortical malformations leading to lifelong epilepsy and neurological comorbidities.
- Mutations in phosphoinositide 3-kinase (PI3K)-ras homolog enriched in brain (Rheb) pathway genes are implicated.
Purpose of the Study:
- To investigate the role of filamin A (FLNA) in TSC and FCDII-related epilepsy.
- To evaluate FLNA-targeting therapies for reducing seizures and neuronal abnormalities.
Main Methods:
- Assessed FLNA expression in human FCDII tissue and mouse models of TSC/FCDII.
- Utilized genetic knockdown of FLNA in mice.
- Administered the FLNA-targeting small molecule PTI-125 to mice before and after seizure onset.
Main Results:
- Increased FLNA expression was observed in FCDII tissue and relevant mouse models.
- FLNA knockdown limited cell misplacement and neuronal dysmorphogenesis in mice.
- FLNA knockdown reduced seizure frequency independently of mTOR signaling.
- PTI-125 treatment alleviated neuronal abnormalities and reduced seizure frequency in mice, even when administered post-seizure onset.
Conclusions:
- FLNA is a potential therapeutic target for epilepsy in TSC and FCDII patients with PI3K-Rheb pathway mutations.
- Targeting FLNA with genetic methods or small molecules like PTI-125 may effectively reduce seizures and associated neurological deficits.
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