BACKGROUND:​

 

 

In my current research I am exploring the role of “Strenuous exercise as a potential risk factor for people with or having a genetic predisposition to ALS/Motor Neuron Disease (MND). ALS (Amyotrophic Lateral sclerosis) is a rare neurodegenerative disease that affects the normal functioning of the nervous system causing damage to upper and lower motor neurons that affects the person’s ability to move and walk. Other disease symptoms of ALS include malnutrition, speech problems, as well as respiratory problems. Globally 268,674 individuals have MND as of 2019 of which majority of cases reported are in UK, Ireland, Australia, Canada, and North America.

 

This disease is fatal and still we do not have a proper cure. So, to limit the progression of this disease the first thing would be to identify the risk factors that may be contributing to this disease. The most common genetic cause of ALS/MND is mutation of the C9orF72 gene. In humans this gene is present in the short (p) arm of chromosome 9 open reading frame 72. This gene is made up of a DNA segment containing 4 guanine and 2 cytosine repeats (GGGGCC) which is known as hexanucleotide repeats. Healthy individuals have 30 hexanucleotide repeats while the patients of ALS/MND have 1000 hexanucleotide repeats. This excessive repeat causes a loss of function as well as a gain of function.

 

The loss of function causes lowering of the C9 protein that is usually present in the neurons present in the brain and spinal cord that leads to motor neuron damage. While the gain of function causes RNA and DPR toxicity. Several animal models have provided clues about role of DPR toxicity as one of the factors driving neurodegeneration. DPRs also known as Dipeptide repeat proteins are present in humans in 5 different forms. These are GP (Glycine-proline), PA(Proline-alanine), GA(Glycine-alanine), PR(Proline-arginine), GR(Glycine-arginine). Out of all 5 the two-arginine rich DPRs (GR and PR) are considered more toxic.

 

Hence, our goal is to identify the pathways in a Drosophila model that leads to ALS/MND. To do so I used a 1000 repeat DPR Drosophila model. I strenuously exercised the flies on a Treadwheel everyday for 2hours for straight 2 weeks and checked their lifespan, motor function, and 24-hour basal activity. Also, to check what happens at the cellular level I checked 12 mitochondrial genes that are known to change with exercise.

 

My early data showed that C9 MND flies with strenuous exercise lives shorter, shows motor defects, and a reduced ability to move and walk.  The gene expression data shows that several important genes that participates in mitochondrial biogenesis, fission, fusion as well in mitophagy showed a down regulation in C9 flies compared to healthy controls. I believe if the risk factors are properly identified this can be translated to successful clinical trials. The findings will help to elucidate the interaction between genetic factors and environmental exposure to strenuous physical exercise in the aetiology of MND.

 

METHODOLOGY:​

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For the initial data, I have used Survival assay, locomotor activity, and real-time qPCR. For the upcoming work, I am using electrophysiology, immunohistochemistry, Mito Sox assay, optogenetics, and Sholl analysis.

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RESULTS:​

 

This shows how I monitor the flies after exercise. I can share a great work done by researchers at Macquarie University in Australia. This was written as a lay summary by me. Please check the link: https://www.readableresearch.com/mnd/vacuumcleanerdrug/

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​​​​​​​​​FUTURE WORK: 

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I am quite optimistic about this work. Initial data was presented at the ENCALS meeting, June 2024 in Stockholm, and we got some great reviews from the ALS members and participants. Our next goal is to publish this in a high impact journal, as well as outreach to wider audience and created awareness about the MND. In future, I would like to strenuously exercise the flies using optogenetics. 

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FUNDED BY:

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​​​CONTACT: 

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