Targeting heat shock response in mouse models of progressive genetic epilepsy

Author interview: Dr. Priyanka Sinha has completed her Ph.D. in neuroscience under the supervision of Prof. S. Ganesh at the department of Biological Sciences and Bioengineering, IIT Kanpur, where she studied the molecular mechanism of epilepsy using mouse models of Lafora disease. Next, she will be joining Harvard Medical School this September to study protein-protein interactions in Alzheimer disease. She is interested in studying neuron-glia interactions and their role in health and disease. In my free time, Priyanka love to read, cook, and watch television series.

How would you explain your paper’s key results to the non-scientific community?

Epilepsy, also known as “fits” in everyday language, is a devastating disease. The episodes of “fits” are known as “seizures.” About 1% of adults and 4% of children have epilepsy worldwide. If we talk about India, more than 1 crore of people in our country are living with epilepsy. Apart from the physical aspect, which is vast in itself, people with epilepsy suffer from the social stigma that affects their psychological well-being.

As we know, electrical conduction in the brain helps us control anything and everything we do. However, when there is abnormal electrical activity due to hereditary or environmental factors, epilepsy occurs. Although epilepsy was diagnosed as a neurological disease in the 18th century, not much is known about the causal factors. Hence, all patients are still treated with palliatives, and anti-epileptic drugs consist of channel blockers that dampen the electrical activity of the entire brain. Long-term treatment with anti-epileptic drugs leads to severe side-effects and compromised brain development. Thus, one needs to study the causative factors of epilepsy to find better therapeutic avenues and help reduce the pain and agony of people who have epilepsy.

For studying epilepsy, various animal models are utilized. We use mouse models of Lafora disease (LD), a fatal progressive myoclonic epilepsy, which begins in teenage (12–16 years of age). It is so severe that the patient dies within a decade of the disease onset. Several pathways are deregulated in LD, and one of them is the heat shock response pathway.

Heat shock response is an elegant protective pathway that is activated whenever our body is exposed to any stress such as infection, starvation, inflammation, environmental toxins, etc. This pathway helps protect the structure of proteins of our body so that these proteins remain functional and control the stress-related damage.

Hence, we wanted to see whether the LD brain has defects in heat shock response. After we established these defects in LD, we administered a drug, dexamethasone, to activate the heat shock response and check whether the treated LD mice have reduced epilepsy. We found that epileptic seizures and neuroinflammation were significantly mitigated. Moreover, as expected, heat shock response-mediated cellular stress was alleviated. Intriguingly, we did not find any reduction in the number of Lafora bodies, the hallmark polyglucosan structures found in LD patients and mouse models.

Thus, we concluded that epilepsy in LD might primarily occur due to stress-induced proteotoxicity. Moreover, it might be secondary to or independent of Lafora bodies.

our initiative can lead to the use of dexamethasone as a potential therapy for epilepsy.

What are the possible consequences of these findings for your research area?

As people with epilepsy are still being treated with palliatives and channel blockers, which have severe side effects, and around 30% of patients develop refractory epilepsy in due course of time, there is a need to develop better therapeutic avenues. In this regard, our initiative can lead to the use of dexamethasone as a potential therapy for epilepsy. As it is an FDA-approved drug, in my opinion, it holds promising results in clinical trials.

What was the exciting moment (eureka moment) during your research?

I remember I was in the darkroom developing the film for western blot when I was probing for HSF1 in the wild type and LD mouse brain samples. As I saw the bands, my first thought was, something went wrong with the LD mouse brain samples. However, when I saw the housekeeping lane, there were six lanes of equal protein. I could not believe my eyes as HSF1 completely vanished in the LD brain samples. I repeated my experiments and ran to my Ph.D. supervisor. Sir has always told me that results are never negative; you must find a way to explain them. I think I will never forget this lesson. I believe this was the eureka moment, and then we started planning further experiments.

What do you hope to do next?

I was fascinated with neuroscience since high school, and I am grateful that I could pursue it further. I want to study the molecular mechanisms of neurological disorders, specifically, the role of neuron-glia interactions in these disorders. In this regard, I will be joining Harvard Medical School, this fall, to pursue the role of PS1-GLT1 interaction in Alzheimer disease pathology.

Where do you seek scientific inspiration?

I like to read stories of all the great inventions we have seen to date. I get inspired by the stories of scientists worldwide as to how they fought against all odds and pursued their scientific endeavors.

How do you intend to help Indian science improve?

In my opinion, we should start with getting children interested in science. I want to teach school kids someday to ignite the scientific flare in their young minds. I believe, if we can get these young minds to start questioning facts around them, we will develop a better and sustainable future for them, which is the need of the hour. Moreover, our country has untapped youth power, which can be harnessed to boost Indian science.

Reference

Sinha P, Verma B, Ganesh S. Dexamethasone-induced activation of heat shock response ameliorates seizure susceptibility and neuroinflammation in mouse models of Lafora disease. Exp Neurol. 2021 Jun; 340: 113656. doi: 10.1016/j.expneurol.2021.113656.

Edited by: Ritvi Shah

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