Saravanan Kolandaivelu, PhD

Research Interests

Research Interests

• Neurodegeneration
• Blinding diseases
• Post-translational lipid modification
• Retinal photoreceptor cells biogenesis, function,  and maintenance
• Na⁺/K⁺ - ATPase in retinal function and stability
• Metabolic changes in neurodegenerative diseases
• Lipid homeostasis

Description of Research

PRCD role in photoreceptor cells maintenance, function and stability:

Our laboratory focused to understand the mechanism behind biogenesis and/or maintenance in the photoreceptor outer segment. Photoreceptor outer segments are modified cilia filled with highly ordered membrane discs that harbor signaling proteins responsible for the detection of photons. It is very puzzling to understand how the photoreceptor OS is maintained and disc membranes are organized and stacked together, which is fundamental for proper function and stability of photoreceptor neurons. Using a combination of physiological, biochemical and molecular multi-disciplinary approaches, including gene editing, animal models, and tissues culture, we strive to understand our long term goal the mechanism behind biogenesis and/or maintenance in the photoreceptor outer segment.

Posttranslational lipid modification “palmitoylation” roles in protein assembly, trafficking, stability, and function:

Our lab studies the importance of the post-translational lipid modification “palmitoylation” in retinal proteins. Among lipid modifications, palmitoylation is the only reversible lipid modification. The dynamic reversibility controls many cellular functions including protein trafficking, protein stability, protein-protein interaction. We will study in retina and identify the proteins which are palmitoylated. Furthermore, our goal is to delineate the mechanism behind palmitoylation in protein trafficking, assembly, and stability.

The importance of Na⁺/K⁺- ATPase in retinal function and survival:

In retinal cells, Na⁺/K⁺-ATPase is an important enzyme that maintain the intracellular Na+, and K+ levels. Using relevant animal models, we study the importance of membrane potential in retinal function and its survival. In gereral, the neuronal cells Na⁺/K⁺-ATPase pump utilizes the 2/3rd of the energy to maintain their function and survival. Interestingly, we identified a non-catalytic “beta units” (ATP1β2) in Na, K-ATPase is post-translationally lipid modified by palmitoylation. However, we do not know the importance of palmitoyl lipid modification and precise role of Na⁺/K⁺-ATPase in retinal function. Therefore, we focused to understand the importance of Na⁺/K⁺-ATPase and palmitoylation in beta subunits (ATP1β2) using retina specific conditional animal models and combination of biochemistry, physiology, molecular, metabolomics and gene therapy approaches.

Understanding the metabolic changes and lipid homeostasis in neurodegenrative diseases:

Any changes/ or defects in metabolic pathways and lipid homeostasis in retinal neurons leads to severe blinding diseases including retinitis pigmentosa and Leber’s congenital amaurosis (LCA) in humans. Using multiple animal models linked with blinding diseases, we study the changes in metabolic and lipid homeostasis in collaboration with Dr. Jianhai Du.  We believe these information is crucial for novel therapeutic treatment for patients with RP and severe blinding diseases. To study in details, we will use systematic approaches including mass-spectrometry, RNA seq, metabolomics studies and imaging analysis.

Grants and Research

Grants:

NIH R01 (2018-2023)

Publications

[2020]

• Emily R. Sechrest, Joseph Murphy, Subhadip Senapati, Andrew F.X. Goldberg, Paul S.-H. Park, and Saravanan Kolandaivelu. Loss of PRCD alters number and packaging density of rhodopsin in rod photoreceptor disc membranes. Scientific Reports, 2020 Oct 21;10 (1):17885. doi: 10.1038/s41598-020-74628-2.

[2019]

• Grenell A, Wang Y, Yam M, Swarup A, Dilan TL, Hauer A, Linton JD, Philp NJ, Gregor E, Zhu S, Shi Q, Murphy J, Guan T, Lohner D, Kolandaivelu S, Ramamurthy V, Goldberg AFX, Hurley JB, Du J. (2019) Loss of MPC1 reprograms retinal metabolism to impair visual function. Proc Natl Acad Sci U S A. Feb 26; 116 (9):3530-3535. doi: 10.1073/pnas.1812941116. Epub 2019 Feb 11.

• Dilan TL, Moye AR, Salido EM, Saravanan T, Kolandaivelu S, Goldberg AFX, Ramamurthy V. (2019). ARL13B, a Joubert Syndrome-Associated Protein, Is Critical for Retinogenesis and Elaboration of Mouse Photoreceptor Outer Segments. J Neurosci. Feb 20; 39 (8):1347-1364. doi: 10.1523/JNEUROSCI.1761-18.2018. Epub 2018 Dec 20. PMID: 30573647

[2018]

• Brooks C, Murphy J, Belcastro M, Heller, D, Kolandaivelu S, Sokolov M (2018). Farnesylation of the transducin G protein gamma subunit is a prerequisite for its ciliary targeting in rod photoreceptors. Front Mol Neurosci, 11:16. PMCID: PMC5787109

• Wen-Tao Deng, Saravanan Kolandaivelu, Astra Dinculescu, Jie Li, Ping Zhu, Vince A. Chioda, Visvanathan Ramamurthy and William Hauswirth (2018). Cone Phosphodiesterase-6γ’ Subunit Augments Cone PDE6 Holoenzyme Assembly and Stability in a Mouse Model Lacking Both Rod and Cone PDE6 Catalytic Subunits. Front. Mol. Neurosci. doi: 10.3389/fnmol.2018.00233 June 2018

[2016]

• Murphy J, Kolandaivelu S (2016). Palmitoylation of progressive rod-cone degeneration (PRCD) regulates protein stability and localization.. J Biol Chem, 291(44):23036-23046. PMCID: PMC5087724
• CHristiansen JR, Pendse ND, Kolandaivelu S, Bergo MO, Young SG, Ramamurthy V (2016). Deficiency of isoprenylcysteine carboxyl methyltransferase (ICMT) leads to progressive loss of photoreceptor function. J Neurosci, 36(18):5107-14. PMCID: PMC4854971
• Murphy D, Kolandaivelu S, Ramamurthy, V, Stoilov P (2016). Analysis of alternative pre-RNA splicing in the mouse retina using a fluorescent reporter . Methods Mol Biol, 1421:269-86.

[2015]

• Murphy D, Singh R, Kolandaivelu S, Ramamurthy V, Stoilov P (2015). Alternative splicing shapes the phenotype of a mutation in BBS8 to cause nonsyndromic retinitis pigmentosa. Mol Cell Biol, 35(10):1860-70. PMCID: PMC4405636

[2014]

• Singh RK, Kolandaivelu S, Ramamurthy V (2014). Early alteration of retinal neurons in Aipl1-/- animals. Invest Ophthalmol Vis Sci, 55(5):3081-92. PMCID: PMC4034756
• Kolandaivelu S, Ramamurthy V (2014). AIPL1 protein and its indispensable role in cone photoreceptor function and survival. Adv Exp Med Biol, 801:43-8.
• Kolandaivelu S, Singh RK, Ramamurthy V (2014). AIPL1, a protein linked to blindness, is essential for the stability of enzymes mediating cGMP metabolism in cone photoreceptor cells. Hum Mol Genet, 23(4):1002-12. PMCID: PMC3900108

[2013]

• Deng WT, Sakurai K, Kolandaivelu S, Kolesnikov AV, Dinculescu A, LiJ, Zhu P, Liu X, Pang J, Chiodo VA, Boye SL, Chang B, Ramamurthy V, Kefalov VJ, Hauswirth WW (2013). Cone phosphodiesterase-6α' restores rod function and confers distinct physiological properties in the rod phosphodiesterase-6β-deficient rd10 mouse. J Neurosci, 33(29):11745-53. PMCID: PMC3713718
• Majumder A, Pahlberg J, Boyd KK, Kerov V, Kolandaivelu S, Ramamurthy V, Sampath AP, Artemyev NO (2013).Transducin translocation contributes to rod survival and enhances synaptic transmission from rods to biopolar cells.Proc Natl Acad Sci USA, 110(30:12468-73. PMCID: PMC3725049

[2011]

• Kolandaivelu S, Chang B, Ramamurthy V (2011). Rod phosphodiesterase-6 (PDE6) catalytic subunits restore cone function in a mouse model lacking cone PDE6 catalytic subunit. J Biol Chem, 286(38):33252-9. PMCID: PMC3190866
• Christiansen JR, Kolandaivelu S, Bergo MO, Ramamurthy V (2011). RAS-converting enzyme 1-mediated endoproteolysis is required for trafficking of rod phosphodiesterase 6 to photoreceptor outer segments.Proc Natl Acad Sci USA, 108(21):8862-6. PMCID: PMC3102416