John Manak, Ph.D.

John Manak, Ph.D.
Associate Professor
Research focus: 

Genetic basis of epilepsy, neurodegeneration, and neurodevelopmental disorders


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One of the primary areas of research in my laboratory is elucidating the genetic basis of neurological disorders, including epilepsy, Alzheimer’s Disease, and neurodevelopmental disorders.  We have found that mutations in the prickle gene cause seizure disorders in fruit flies, similar to those observed in mice and humans with orthologous Prickle mutations, and we are now using the fly model to perform both directed and unbiased genetic screens to identify other components in the seizure pathway, as well as elucidate the mechanism responsible for the disease phenotype. We have shown that mutations affecting different isoforms of the fly prickle gene have opposite behavioral phenotypes; remarkably, mutation of the pksple isoform makes flies susceptible to seizures, whereas mutation of the pkpk isoform actually makes the flies less susceptible to seizure activity.  This suggests that tipping the balance of prickle isoforms in one direction can drive the seizure phenotype, and consistent with this hypothesis we have been able to create an epileptic fly simply by increasing the pkpk isoform exclusively in neurons and muscles (mimicking the imbalance we see in the pksple mutants).  We have analyzed the electrophysiology of the prickle mutants in collaboration with Chun-Fang Wu's lab and have found that the pksple mutants.  In a recently published study, we show that anterograde vesicle transport in neurons is enhanced in the pksple seizure-prone mutants, and that we can fully suppress the seizure phenotype by reducing the dose of either of two Kinesin subunits, which make up the motor responsible for anterograde transport.  These data reveal a new pathway in the pathophysiology of seizure disorders, and have also provided several intriguing connections to neurodegeneration.  Since roughly one third of epilepsy patients have adverse effects from the drugs that are currently available, and since some of the more popular drugs have been associated with birth defects, there is a great need to develop safer and more effective anti-epileptic medications. We are thus using the pksple flies to screen novel anti-epileptic drugs; our pipeline from fly to mouse to human will allow us to move from one system to the other as we begin to identify molecules that promote anti-seizure activity.  Although not described here, additional work in my laboratory is focused on using fruit fly genetics to functionally validate human gene mutations associated with neurodevelopmental disorders such as ID (intellectual disability) and ASD (autism spectrum disorders).

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