Visvanathan Ramamurthy, PhD

Research Interests

Protein folding, modification in neurodegenerative diseases and ciliopathies

Protein Folding: We want to identify the significance of Heat shock protein 90 (HSP90) mediated protein folding in photoreceptor neurons. Our interest in HSP90 stems from the recent use of HSP90 inhibitors for treatments of neurodegenerative diseases and cancer. In cancer trials, patients complain of night vision loss, alluding to the need for HSP90 for normal vision. To uncover the link between the need for HSP90 and vision, we generated an animal model lacking HSP90 using CRISPR-Cas9.

Protein Assembly and Interactome: Proteins function as an extensive network to evoke a particular function. Our goal is to map in vivo the protein networks in the photoreceptor neurons and how these networks change during disease.

Protein post-translational modification and function: Modifications of proteins enhance their diversity and impart unique functionality. Interestingly, several diseases are linked to defective protein modifications. Recently, we have focused on protein glutamylation, as this modification is reversible, potentially playing a dynamic role in the cell. Using a combination of mass-spectrometry, animal models, etc., we are testing the importance of this modification in photoreceptor neurons.

Protein Trafficking: Our human eye contains around 120 million photoreceptor cells (rods/cones). Each of these cells moves proteins at an astonishingly rapid rate (1000 molecules per second in each cell), yet we know little about this process. Following are some interesting questions we are trying to answer:

How do proteins move at this rapid pace? What are the molecular motors that drive this movement?

How does post-translational lipid modification help to retain proteins in different compartments? 

Tubulinopathies: Protein diversity can also be achieved by encoding proteins with minor changes to fit the task. A classic example is the expression of multiple tubulin isoforms that make up the microtubules. Mutations in several tubulin isoforms lead to defective brain development, pointing to the unique need for these isoforms in neurons. We have confirmed this with one of our animal models; we hypothesize that defective Cerebrospinal Fluid (CSF) movement in the brain leads to this phenotype. Besides, mutations in tubulin lead to sensory defects, including vision and hearing. Our goal is to understand the mechanism behind the tublinopathies that leads to hearing loss and defective brain development

Our approach: We use a combination of animal and cell culture models generated by CRISPR-Cas9. Our comprehensive experimental strategy includes electrophysiology, morphology (by High-resolution imaging/Electron microscopy), biochemical, biophysical, and molecular approaches.

Grants and Research

        This project will investigate how RNA binding proteins boost protein expression in photoreceptor cells to enable vision, an unexplored aspect of the photoreceptor cell biology. Our work will allow us to better understand how photoreceptors function and how blinding disease develops. We expect that the results of this study will open new ways to treat blinding diseases

HRSA – Congressionally Directed Spending (CDS)

Co-PI (or POC), Visual Impairment and intervention Strategies, $1,160,000.00

Helps to purchase a mass-spec and TEM.

Collaborators: Karen Martin, Peter Perotta and Jianhai Du.

Publications

[2023]
 

• Munezero D, Aliff H, Salido E, Saravanan T, Sanzhaeva U, Guan T, Ramamurthy V. HSP90α is needed for the survival of rod photoreceptors and regulates the expression of rod PDE6 subunits - PubMed (nih.gov) J Biol Chem. 2023 May 10:104809. doi: 10.1016/j.jbc.2023.104809. Epub ahead of print. PMID: 37172722.
• Moakedi F, Aljammal R, Poria D, Saravanan T, Rhodes SB, Reid C, Guan T, Kefalov VJ, Ramamurthy V. Prenylation is essential for the enrichment of cone phosphodiesterase-6 (PDE6) in outer segments and efficient cone phototransduction - PubMed (nih.gov) Hum Mol Genet. 2023 Jun 29:ddad108. doi: 10.1093/hmg/ddad108. Epub ahead of print. PMID: 37384398.

[2022]

• Matalkah F, Jeong B, Sheridan M, Horstick E, Ramamurthy V, Stoilov P. The Musashi proteins direct post-transcriptional control of protein expression and alternate exon splicing in vertebrate photoreceptors - PubMed (nih.gov). Commun Biol. 2022 Sep 24;5(1):1011. doi: 10.1038/s42003-022-03990-w. PMID: 36153373; PMCID: PMC9509328.
• Matalkah F, Rhodes S, Ramamurthy V, Stoilov P. The mAB 13A4 monoclonal antibody to the mouse PROM1 protein recognizes a structural epitope - PubMed (nih.gov) PLoS One. 2022 Oct 10;17(10):e0274958. doi: 10.1371/journal.pone.0274958. PMID: 36215230; PMCID: PMC9550058.

[2020]