DEPDC5 as a potential therapeutic target for epilepsy

ABSTRACT

Introduction: Dishevelled, Egl-10 and Pleckstrin (DEP) domain-containing protein 5 (DEPDC5) is a protein subunit of the GTPase-activating proteins towards Rags 1 (GATOR1) complex. GATOR1 is a recently identified modulator of mechanistic target of rapamycin (mTOR) activity. mTOR is a key regulator of cell proliferation and metabolism; disruption of the mTOR pathway is implicated in focal epilepsy, both acquired and genetic. Tuberous sclerosis is the prototypic mTOR genetic syndrome with epilepsy, however GATOR1 gene mutations have recently been shown to cause lesional and non-lesional focal epilepsy.

Areas covered: This review summarizes the mTOR pathway, including regulators and downstream effectors, emphasizing recent developments in the understanding of the complex role of the GATOR1 complex. We review the epilepsy types associated with mTOR overactivity, including tuberous sclerosis, polyhydramnios megalencephaly symptomatic epilepsy, cortical dysplasia, non-lesional focal epilepsy and post-traumatic epilepsy. Currently available mTOR inhibitors are discussed, primarily rapamycin analogs and ATP competitive mTOR inhibitors.

Expert opinion: DEPDC5 is an attractive therapeutic target in focal epilepsy, as effects of DEPDC5 agonists would likely be anti-epileptogenic and more selective than currently available mTOR inhibitors. Therapeutic effects might be synergistic with certain existing dietary therapies, including the ketogenic diet.

KEYWORDS:

• DEPDC5
• focal epilepsy
• NPRL2
• NPRL3
• GATOR1
• mechanistic target of rapamycin
• tuberous sclerosis
• cortical dysplasia
• rapamycin

Article highlights

• Dysfunction of the mTOR pathway occurs in tuberous sclerosis and other genetic syndromes, focal cortical dysplasia, non-lesional focal epilepsy, as well as post-traumatic epilepsy.

• DEPDC5 is a subunit of the GATOR1 complex, which selectively inhibits mTORC1 during periods of amino acid deprivation.

• Existing mTORC1 inhibitors such as rapamycin have shown promise in treatment of focal epilepsy associated with tuberous sclerosis, and might also be effective for other focal epilepsy syndromes.

• Agonists of DEPDC5 could theoretically have an anti-epileptogenic effect in certain types of focal epilepsy by inhibiting mTORC1 in an amino acid-dependent manner. This selective inhibition might allow for fewer side effects when compared to existing direct mTORC1 inhibitors (i.e. rapamycin).

• Though DEPDC5 agonism is an appealing therapeutic mechanism, considerable work in drug development is required, and such therapies would need to be superior to rapamycin analogs or other existing therapies in terms of efficacy and tolerability.

This box summarizes key points contained in the article.

Declaration of interest

K. A. Myers has received a travel grant from Zynerba. I. E. Scheffer has received payments from UCB Pharma, Athena Diagnostics and Transgenomics for lectures and educational presentations. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

K. A. Myers receives funding from a Citizens United for Research in Epilepsy Taking Flight Award. I. E. Scheffer is funded by an NHMRC Program Grant (628952) and holds an NHMRC Practitioner Fellowship (1006110).