The Role of Alzheimer’s disease relevant Tau modifications in neurodegeneration and mitochondrial dysfunction

Dr. Sanjib Guha’s interview with Bio Patrika hosting “Vigyan Patrika”, a series of author interviews. Dr. Guha is currently a Postdoctoral research associate in the Department of Anesthesiology & Perioperative Medicine, University of Rochester Medical Center, Rochester, USA. He published a paper titled “ Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model” as the first author in Molecular Neurodegeneration journal (2020). Dr. Guha also published a review article titled “ The crosstalk between pathological tau phosphorylation and mitochondrial dysfunction as a key to understanding and treating Alzheimer’s disease “ in Molecular Neurobiology journal (2020) as corresponding author.

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

Our lab’s research focuses on Alzheimer’s disease (AD), and our protein of interest is tau. In physiological conditions, tau protein is extremely beneficial for maintaining neuronal integrity, structure, and function. When there are certain post-translational modifications (PTMs) at specific sites/ epitopes on the tau protein, our recent discovery has shown that it converts it to a toxic pathogenic protein. In our lab, we use tiny nematode worm species called C. elegans as the genetic model organism. We introduced wild-type human tau into its genome with the help of the “single-copy gene-insertion” technique. With the CRISPR/Cas9 gene-editing tool, we introduce site-specific disease mutations on the tau protein to mimic different PTMs such as phosphorylation and acetylation ( Fig. 1). Broad conservation and disease relevance have helped our model system mimic different pathological phenotypes such as behavioral abnormalities and neurodegeneration solely in the worms carrying these toxic mutations/tau modifications. Interestingly, we have further demonstrated that the modified tau protein severely impacts mitochondrial health, which further aids in the progression of this severe neurodegenerative disorder. This has led us to uncover novel molecular pathways and logic by which pathological tau impair neuronal shape and function.

Figure 1. CRISPR/Cas9 modified tau mutants demonstrate mitochondrial dysfunction, as well as the formation of tau aggregates. These can lead to severe neurodegeneration, as demonstrated by the neurons’ functional decline and morphological abnormalities. All these can be the backbone behind Alzheimer’s disease.

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

Our study has shown a mechanistic connection between toxic tau and mitochondria and how it leads to neurodegeneration. This link was missing before, as researchers knew that toxic tau is bad for neuronal health, but exactly how it causes neurodegeneration was unknown. We have focused on certain PTMs such as phosphorylation and acetylation and specific pathogenic sites such as Threonine 231(T231E) and Lysine 274 and 281 (K274/281). These epitopes can be potentially targeted by immunotherapy and other pharmacological inhibitors, such as acetylation modulators and kinase inhibitors.

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

Mitophagy is a dynamic cellular mechanism that helps the cell in removing damaged and dysfunctional mitochondria. Mitochondrial stressor (such as paraquat, an inhibitor of Complex I) further upregulates mitophagy because cells want to eliminate unhealthy mitochondria. Interestingly, our tau-mimetic worms failed to respond to this stress, where mitophagy was not upregulated, indicating further accumulation of damaged mitochondria within the neurons. This phenomenon has been described as “system overload” in the human brain, where mitochondrial damage can’t be dealt with effectively in a diseased brain. Astonishingly, we could phenocopy this mechanism in the worm genetic model using a fluorescent probe called mito-mKeima, specifically targeted to the mitochondrial matrix.

What do you hope to do next?

Our uncovering of the underlying machinery led us to find that pathologic modified tau actively pruning to control neuron shape and function. In our current study, we are introducing a motif (44-amino acid) called Degron via CRISPR/Cas9 technology, which specifically binds to the toxic tau species and directs them to proteosome for further degradation in the presence of a phytohormone, auxin. This will tell us, when the toxic tau gets degraded, whether the pathological phenotypes get rescued or not. Moreover, since C. elegans is an excellent tool for drug screening, in future, we plan to do a broad screening of drug molecules, targeting to bolster mitochondria health and simultaneously degrade any tau aggregates. This is a combinatorial approach that we would like to pursue, where we can target both the causal mechanisms of AD ( Fig. 2).

Figure 2. C. elegans as a platform for therapeutic screening, targeting two different aspects of AD: improving mitochondrial health and removing tau aggregates. We will try the drug cocktail approach at appropriate doses on neuronal cell lines followed by testing on higher model organisms such as rats and mice if successful.

Where do you seek scientific inspiration?

I drew my scientific inspiration from my grandfather, a Civil surgeon, and my father, a government-employed Electrical Engineer, serving West Bengal State Electricity Board for several years. I learned how to work diligently, with full passion and dedication, and, most importantly, honestly! Although they belong to different education fields from mine, they are my inspiration in many aspects of my life and motivate me to work hard daily. My wife, Sree, just in her 30s but is already a faculty member at the University of Rochester on top of being a senior Embryologist at Strong Memorial Hospital. I have seen tremendous growth in her career, and she has achieved so many milestones, which makes me incredibly proud and happy.

How do you intend to help Indian science improve?

Whenever I visit India for a quick trip, I generally give scientific talks at many Universities. There I discuss with India’s bright minds how to pursue a scientific career, the different ways, and opportunities. I am incredibly grateful to my Alma mater, Heritage Institute of Technology, Kolkata (HITK), to shape my career path and provide all the support and needs for me to pursue higher education abroad. I have created a HITK alumni group, where one Sunday a month, I organize the alumni’s seminars, and current students and faculties all participate in that. Moreover, I am part of an organization called Freedom English Academy (FEA). Every month, I sit down with the students over Zoom and help them improve their English and other soft skills such as acing interviews, editing resumes, SOPs, etc. We also brainstorm how they can pursue their higher education and follow different scientific paths.

Reference

Guha S, Fischer S, Johnson, G V W and Nehrke K. Tauopathy-associated tau modifications selectively impact neurodegeneration and mitophagy in a novel C. elegans single-copy transgenic model. Mol Neurodegeneration 15, 65 (2020).

Guha S*, Johnson G VW, and Nehrke K. The Crosstalk Between Pathological Tau Phosphorylation and Mitochondrial Dysfunction as a Key to Understanding and Treating Alzheimer’s Disease. Mol Neurobiol 57(12) (2020).

Email: sanjibcsu@gmail.com

Originally published at http://biopatrika.com on November 16, 2020.

Bio- Biology; Patrika: Magazine. An integrated platform for “Vigyan patrika”, “Margdarshak”, “BioKonnect” and “Jobs”. Indian Science highlights.

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