The theme of our lab's research is how aggregation can control different physiological processes.

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The specific problem we are interested is understanding the mechanism of long lasting memory. The question here is how molecules having a limited half life can maintain memory over a duration of life time. Our previous work has shown the prion-like properties associated with a protein synthesis regulator Orb2 is crucial for this. Interfering with the prion-like aggregation blocks persistence of long lasting memory without effecting its formation. We are currently working on understanding the upstream and downstream molecular mechanism associated with Orb2. Below is a list of questions we are addressing in our lab.

 

What controls oligomerization of Orb2?

 

We hypothesized as oligomerization of Orb2 is a protein folding problem, molecular chaperones may play a role in this. We have identified a Hsp40 family chaperone protein Mrj, as a crucial regulator of oligomerization of Orb2 in the brain. We generated a CRISPR mediated deletion of Mrj  and found that these animals have a deficit in long term memory. Currently we are focusing on understanding the molecular mechanism of Mrj dependent Orb2 oligomerization in more details. 

 

What mediates consolidation of long term memory?

 

A single training can result in short term memory formation whereas long term memory needs multiple spaced training. We are asking what molecular mechanisms contribute towards the conversion of short term to long term memory or consolidation of memory. We are using behavior experiments along with screening for novel neurotransmitter receptors to understand this. We have identified a previously understudied receptor in this process and are currently focusing on identifying the neural circuitry involved in this.

 

Can biomolecular condensates play a role in neurodevelopment?

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Using the eye development pathway as a model, we are attempting to understand if formation of biomolecular condensates play any role in this pathway. Our work suggests that a transcriptional-co-activator forms biomolecular condensates which play a role in transcriptional regulation associated with eye development. We are further working on understanding the mechanism of such condensate formation and how they might regulate eye development.

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What role RNA binding proteins play in Huntington's disease?

 

Huntington's disease is a neurodegenerative disease caused due to expansion of poly Q repeats which cause the protein to aggregate. This disease has no treatment till date. Previously we found Orb2 to be sequestered in Huntingtin aggregates and co-expression of Orb2 results in partial rescue of pathogenic Huntingtin expressing animals. We found that pathogenic Huntingtin aggregates cause a protein synthesis deficit in cells, and the Orb2 mediated rescue is through improving the translation deficit. We are now screening for more RNA binding proteins which can be sequestered by Huntingtin aggregates and focusing on what molecular pathways get effected during this. We hope identification of these candidates will provide us with new pathways which can be potential targets for treating the disease in future.

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Identification and characterization of modifiers of Fus associated neurotoxicity

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Aggregation of Fus is associated with two neurodegenerative diseases ALS and FTD. using genetic screens we identified modifiers of Fus associated neurotoxicity and are currently attempting to understand what might be the mechanism of this rescue will be.

 

Techniques we use:

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​The tools that we use range from molecular biology, protein purifications, protein biochemistry, imaging, fly genetics and behavior.