miRNA compartmentalisation paves a new avenue in neuroinflammatory process of Alzheimer’s Disease

Mr. Dipayan De’s interview with Bio Patrika hosting “Vigyaan Patrika”, a series of author interviews. Dipayan is from CSIR-Indian Institute of Chemical Biology, Kolkata. He started his Science journey from St. Xavier’s College, Kolkata where he undertook a bachelor’s degree in Science majoring in Microbiology and went onto do a Master’s in Biochemistry at University of Calcutta. Currently, he is pursuing his Ph.D. under the supervision of Dr. Suvendra Bhattacharyya at CSIR-Indian Institute of Chemical Biology, Kolkata. From the very beginning, his specific scientific interest in the field of small RNA was nurtured by his mentor Dr. Bhattacharyya. Under the eminent guidance of Dr. Bhattacharyya, he delved into exploring the details of how cellular organelles regulate small RNA activity in mammalian cells. One of his recent findings highlights how mTOR reactivation improves memory and disease pathology by regulating miR-146a activity in Alzheimer’s disease brain that has been published in Molecular Therapy: Nucleic Acids (De et al., 2021). He fosters a deep passion in the imaging field and would like to dig deep into the fascinating realms of microscopy in the future. When not in the laboratory, Dipayan is an ardent foodie and loves to travel. Here in this interview, Dipayan discusses his new findings “Amyloid-β oligomers block lysosomal targeting of miRNPs to prevent miRNP recycling and target repression in glial cells ” published in “Journal of Cell Science”.

Listen audio

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

Major challenges for Alzheimer’s disease (AD) patients include forgetfulness and decline in motor activities. The pathological hallmark of Alzheimer’s disease these patients include Amyloid β plaque formation in the brain, resulting in neurodegeneration and loss of neurons in the central nervous system. One of the major reasons for neurodegeneration is the occurrence of uncontrolled inflammation within the brain. There are star-shaped glial cells known as astrocytes present around the neurons which regulate this inflammatory process via the expression of cytokines. Within these glial cells, tiny RNA molecules known as miRNA are present which can repress the expression of cytokine mRNA and thus regulating the inflammation process. However, with the exposure of amyloid-β plaques there is an increase in the expression of miRNA and cytokine mRNA within glial cells. In this study, we asked that in spite of the increase in miRNAs expression within astrocytes, why the cytokine production fails to decline in order to subside the inflammation process. Interestingly, we found that, although present in abundance, the miRNA activity is diminished within glial cells when exposed to amyloid-β plaques. Furthermore, miRNA fails to bind to their target cytokine mRNA because of differential localization inside the cell. β-amyloid treated glial cells show a faulty endosome maturation pathway which leads to compartmentalization of miRNA and their target mRNA into two separate cellular compartments. We found miRNA along with the Ago2 protein present inside the early endosome but cytokine mRNAs to be associated with the endoplasmic reticulum-associated polysomes. Such segregation of miRNA from their cytokine mRNA results in target de-repression thus triggering an uncontrolled inflammation in the diseased neurons. This phenomenon subsequently leads to the demise of the neuronal cells.

Figure 1. Aβ disrupts miRNP recycling to increase cytokine production in glial cells

One of the most interesting findings from our study is how endosome maturation can regulate miRNA activity.

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

One of the most interesting findings from our study is how endosome maturation can regulate miRNA activity. Our findings in Alzheimer’s disease system showed how a cell biological process like vesicular trafficking has the potential to fine tune the gene expression process within the cell. Similar phenomenon can be speculated for other neurodegenerative disease which need to be investigated further. Another interesting aspect is that miRNA with RNA binding proteins phase separated to form specialized RNA aggregates known as processing Bodies or P Bodies. Presence of RNA aggregates can be found in many neuronal and non-neuronal diseases. These phase separated bodies not only act as storage sites of RNA and RNA binding proteins but also create a micro environment for other cellular functions such as different forms of cell signalling. Furthermore, we also found that depletion of P-Bodies relieves the AD associated inflammation process in glial cells which indicates that RNA granules can play an important role in the progression of these neurodegenerative diseases or any other diseases that associate with increased inflammation.

Figure 2. Phase separated RNA granules in yellow (P-body) can be seen throughout the cytoplasm where endocytic pathway has been disrupted

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

Functional assays showed lower miRNA activity in the amyloid exposed glial cells. Interestingly, all the three major component of the repression system i.e. miRNA, major repression protein Ago2 and target mRNA were found to be abundant in the cell. Moreover, the association between Ago2 and miRNA that forms the functional miRNPs was also found to be intact. For a long time we were struggling to figure out why in spite of all the machinery of the repression system being in order, there was a drop in miRNA activity? The first break that we got was when we fractionated the cell and tried to find out localization of all the three components. Cell fractionation assay first showed us although all the three components are present, yet they are localized in the different compartments of the cell. The fact that cellular compartmentalization can cause a problem in the miRNA activity was pretty exciting. We went on and found endo-lysosomal fusion has a role on target mRNA recognition, which is pretty novel.

What do you hope to do next?

Currently, I am on the verge of submitting my thesis for the completion of my Ph.D. Also, I am looking for a post-doctoral position that will help me expand my microscopy and biochemistry knowledge especially in the field of molecular cell biology. In the long run, I see myself running a laboratory to explore some of my ideas in the field of cell biology. 

Where do you seek scientific inspiration?

I have been very privileged through out my Ph.D. to be surrounded by dynamic and visionary people in the field of science. I believe that multifaceted factors have shaped CSIR-IICB to become a great place to do science. My supervisor Dr. Suvendra Bhattacharyya had a big impact on my Ph.D. career both on and off the laboratory. His teachings imparted me the ability to think critically while proceeding with the scientific problem and the propensity to ask relevant questions regarding the research problems. Additionally, I had fantastic lab mates and lab seniors who have been really fun to work with. Last but not least my wife, Subhalakshmi Guha, a Ph.D. student in the field of neuroscience has been a huge support and motivation for me throughout.

How do you intend to help Indian science improve?

If we look at the sheer number of talented scientists, doctors, and engineers in different fields in this country and their intelligence, India possesses huge potential for scientific greatness. Nowadays science has become multi-disciplinary and to answer a scientific question all the different fields of science need to merge together. A good collaborative environment between the different fields of science can help us immensely. Also, we need to find the right balance between basic and translational research so that the findings of the desk can be implemented in the right manner to improve human life.

Reference

Dipayan De, Suvendra N. Bhattacharyya; Amyloid Beta oligomers prevents Lysosomal targeting of miRNP to stop its recycling and target repression in glial cells. J Cell Sci 2021; jcs.258360. doi: https://doi.org/10.1242/jcs.258360

Lab website: https://iicb.res.in/faculty/suvendra-bhattacharyya

Edited by: Sukanya Madhwal

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: