Meet Nibha Mishra: A Bright, Young ALS Researcher

In recognition of ALS Awareness Month – with a theme of “Raise Your Voice” – we’re sharing new stories nearly every day in May. They’re stories about people living with the disease and their caregivers, the volunteers and health care providers who help make the lives of people with ALS better, the generous fundraisers and the participants in Walk to Defeat ALS and Team Challenge ALS events, and the researchers fighting for a cure. They are all part of our ALS community, helping us fight toward a world without ALS. This is the seventh profile in that series.

The ALS Association is happy to continue our tradition of supporting bright, young scientists in ALS research through our Milton Safenowitz Postdoctoral Fellowship Program. These awards encourage young scientists to enter and, importantly, to remain in the ALS field.

We are proud that 90 percent of our funded postdoctoral fellows go on to start their own ALS research labs and continue to mentor more young scientists, further adding innovative ideas to the field.

This year, we are supporting six new postdoctoral fellows out of a highly competitive applicant pool. This is the fourth in a series of six articles highlighting the dedication and unique contribution each fellow makes to ALS research, while getting to know the person behind the lab coat.

Today, we sit down with Dr. Nibha Mishra from Massachusetts General Hospital and Harvard Medical School to learn about her unique research project aimed at understanding disease pathways associated with ALS fused in sarcoma (FUS) gene mutations.

Nibha Mishra, Ph.D.
Massachusetts General Hospital & Harvard Medical School
Mentor: Dr. Clotilde Lagier-Tourenne

Project: Identifying determinants of FUS nucleocytoplasmic localization by CRISPR/Cas9 genetic screen in ALS patient cells

What is your message to our generous donors?

I’m extremely honored and grateful to receive the Milton Safenowitz Postdoctoral Fellowship from The ALS Association. I believe this encouraging support will allow me to expand my expertise in the ALS field with the goal to develop efficient therapeutic approaches for this disease. I will use state-of-the-art technologies to identify genes that influence the cellular localization of RNA-binding proteins for the development of new ALS disease therapies.

Why did you choose to focus on ALS research and what do you like about working in this field?

Since high school, I’ve always wanted to participate in the scientific research focused on neurological diseases. I was drawn to studying the mechanisms of neuronal death by extreme severity and absence of efficient treatment in neurodegenerative diseases.

Joining Dr. Lagier-Tourenne’s laboratory from my postdoctoral training provided me with the perfect environment to work on the challenging questions of ALS disease. I really enjoy working at Mass General Hospital, where we frequently meet and discuss the clinical and basic science research developments to explore innovative ALS therapeutic strategies.

Do you do any volunteer work for the ALS community?

With the support of my mentor and clinicians at Mass General Hospital, I have the opportunity to visit the ALS clinic. Discussing with the patients allows me to better understand their journey with ALS and to share the progress of our research efforts. I am grateful for these interactions that motivate me to the urgency to find a cure for such a devastating disease.

Briefly describe your funded research project.

FUS mutations and its cytoplasmic mislocalization are associated with ALS and frontotemporal dementia (FTD) and are responsible for the most aggressive juvenile forms of ALS. The FUS protein is normally located in a cell’s nucleus but accumulates in the cytoplasm of affected cells from ALS patients, called cytoplasmic mislocalization. Accumulating evidence supports that cytoplasmic mislocalization of FUS causes toxicity that is crucial for motor neuron death. However, the factors influencing abnormal nucleocytoplasmic transport (i.e. transport between the nucleus and the cytoplasm) of FUS remain elusive.

Dr. Lagier-Tourenne and collaborators have previously demonstrated that FUS plays a major role in regulating RNA processing and identified FUS-dependent alterations in levels or splicing of messenger RNAs (mRNAs).  Abnormal RNA processing is found in the central nervous system of ALS mouse models, as well as in the skin cells (fibroblasts), and neurons from ALS patients carrying FUS mutations.

The goal of my project is to use a genetic screen to uncover new pathways influencing FUS cellular localization in patient cells. I will take advantage of the extraordinary efficiency of the CRISPR/Cas9 system to inactivate each of the ~20,000 genes in the genome and determine which genes restore a normal FUS nuclear localization in patient cells. I will then test whether these genes also modulate the cellular localization of other RNA binding proteins altered in ALS, such as TDP-43.

What is the impact of your research on the ALS community?

The goal of my research is to use an unbiased genome-wide approach to identify pathways that were not suspected to be involved in ALS and may represent new targets for therapeutic development. I will use the cutting-edge gene-editing technology, called CRISPR/Cas9, to elucidate some mechanisms leading to the abnormal nucleocytoplasmic transport of RNA binding proteins associated with ALS. A better understanding of the molecular events perturbed in ALS is crucial to [developing] new therapeutic avenues for ALS patients.

Tell me something unique about yourself.

I grew up in a small city in India. My journey outside India started with my husband, Arijit Basu, who is a postdoctoral researcher at Massachusetts Institute of Technology, and our two-year-old daughter, Yashita Basu. After obtaining our respective doctoral degrees in India, we both had opportunities to initiate our postdoctoral training at the Hebrew University in Jerusalem, Israel.

My postdoctoral research with Professor Hermona Soreq at the Hebrew University seeded my interest in post-transcriptional regulation of genes in neurodegenerative diseases. I pursued this interest and joined the laboratory of Dr. Lagier-Tourenne at Massachusetts General Hospital and Harvard Medical School.

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