Dr. Reddy P. Kommaddi


Senior Scientific Officer

I graduated with a PhD in Neuroscience from National Brain Research Centre, India. I went on to pursue post doctoral training at the Montreal Neurological Institute (MNI), McGill University, Montreal, Canada as a CIHR Canada-HOPE International Postdoctoral Scholar and Department of Medicine, Duke University Medical Centre, Durham, NC, USA. I returned to India and joined as a Ramalingaswami Fellow at the Centre for Neuroscience, Indian Institute of Science, Bangalore and focused on elucidating the early pathogenic mechanisms involved Alzheimer’s disease. In 2020 I moved to Centre for Brain Research and continuing research on identifying critical factors and molecular mechanisms involved far before the clinical symptoms manifest in Alzheimer’s disease.

Cellular and molecular pathogenic mechanisms of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most predominant form of dementia. It is predicated by 2050, 131.5 million people i.e., 9.4% of the world population might be afflicted with AD. It is characterized by a progressive decline in memory and other higher order cognitive functions. Neuropathological hallmarks of AD include intracellular neurofibrillary tangles, extracellular beta-amyloid plaques, cerebral atrophy, gliosis, and extensive neurodegeneration, loss of dendritic spines and synaptic dysfunction. There is currently no cure or treatment to slow down its progression. Emerging evidences from patients suggest that AD pathologies may be observed several years prior to clinical symptoms manifest. Thus, identifying critical molecules involved in the initial stages may help to detect it early and develop drugs that delay its onset or slow it down, allowing patients to lead a better quality of life. The overall interest of the laboratory is to understand the pathogenic mechanisms underlying these disorders with a goal to develop disease-modifying therapies.

Dendritic spines along the neurites are the primary sites for receiving information and cellular substrates for synaptic plasticity. These spines undergo synaptic activity-dependent modifications, such as enlargement and shrinkage/elimination during long-term synaptic potentiation or long-term synaptic depression, respectively, and they correlate with memory deficits in animal models. Filamentous actin, (F-actin), is the major cytoskeletal protein in the spines and spine structure is regulated by remodelling of actin cytoskeleton during LTP/LTD. We used APP/PS1 mice to show recall memory deficits and primary neurons from WT and APP/PS1 mice to examine the spine density and nanoscale organization of F-actin in spines.

Confocal image shows F-actin staining of dendritic spines and dendritic spine density.  Reconstructed images of mushroom spines from WT and APP/PS1 and dSTORM reveal perturbation of F-actin nanoarchitecture at mushroom spine heads. Confocal microscopy is used to visualize activity dependent protein translation in neurons using fluorescently labeled proteins. Long term fear memory deficits were observed in APP/PS1 mice.

Synaptosomes preparations are pinched-off ends of neurites with biochemical integrity. These preparations are a good starting material for functional and biochemical assays.  The accompanying picture (left) is an electron micrograph of a synaptosome prepared in the lab. The lab undertakes transcriptomic studies (right) with human and mouse samples to identify novel pathways that might be implicated in the progression of AD.

Understanding the sex specific differences in Alzheimer’s disease pathology

The incidence of Alzheimer’s disease (AD) is higher in women as compared to men. This has often been attributed to the longer life span of women compared to men. Although neuroprotective effect of estrogen is well established, the underlying molecular and pathogenic mechanisms explaining the higher burden of AD in postmenopausal women are unclear. Synaptic dysfunction is considered to occur several years prior to the appearance of the pathophysiological and behavioural symptoms of AD. Recently, we have investigated one of the major cytoskeleton proteins, F-actin and it is highly enriched in dendritic spines. Perturbation of F-actin levels at synapse leads to the alteration of dendritic spine structure and impairment of recall cognitive functions. We are primarily focusing on investigating the sex-specific differences through the progression of the disease using AD mouse models. Additionally, we are trying to understand how estrogen regulates cognitive functions, synaptic plasticity and identify molecular cascades to determine potential targets for AD intervention.

Ramya M
PhD Student

 

 

 

  1. Verma A, Ray A, Bapat D, Diwakar L, Kommaddi RP, Schneider BL, Hirsch EC, and Ravindranath V. Glutaredoxin 1 Downregulation in the Substantia Nigra Leads to Dopaminergic Degeneration in Mice. Movement Disorders. 2020. Oct; 35(10):1843-1853.
  2. Kommaddi RP, Deepika ST, Karunakaran S, Bapat D, Nanguneri S, Ray A, Schneider BL, Nair D, Ravindranath V. Glutaredoxin1 diminishes amyloid beta mediated oxidation of F-actin and reverses cognitive deficits in an Alzheimer’s disease mouse model. Antioxid Redox Signal. 2019. Dec 20;31(18):1321-1338.
  3. Ahmad F, Das D, Kommaddi RP, Diwakar L, Gowaikar R, Rupanagudi KV, Bennett DA, Ravindranath V. Isoform-specific hyperactivation of calpain-2 occurs presymptomatically at the synapse in Alzheimer’s disease mice and correlates with memory deficits in human subjects. Sci Rep. 2018 Sep 3;8(1):13119.
  4. Kommaddi RP, Das D, Karunakaran S, Nanguneri S, Bapat D, Ray A, Shaw E, Bennett DA, Nair D, Ravindranath V. Ab mediates F-actin disassembly in dendritic spines leading to cognitive deficits in Alzheimer’s disease. J Neurosci. 2018. Jan 31;38(5):1085-1099.
  5. Jean-Charles PY, Yu S, Abraham D, Kommaddi RP, Mao L, Strachan RT, Zhang ZS, Bowles DE, Brian L, Stiber J, Jones S, Koch WJ, Rockman HA, Shenoy SK. Mdm2 regulates cardiac contractility by inhibiting GRK2-mediated desensitization of b-adrenergic receptor signaling. JCI Insight. 2017; 2(17):e95998.
  6. Ahmad F, Singh K, Das D, Gowaikar R, Shaw E, Ramachandran A, Rupanagudi KV, Kommaddi RP, Bennett DA, Ravindranath V. ROS-mediated loss of synaptic Akt1 signaling leads to deficient activity-dependent protein translation early in Alzheimer’s disease. Antioxid Redox Signal. 2017; 16:1269-1280.
  7. Feger BJ, Thompson JW, Dubois LG, Kommaddi RP, Foster MW, Mishra R, Shenoy SK, Shibata Y, Kidane YH, Moseley MA, Carnell LS, Bowles DE. Microgravity induces proteomics changes involved in endoplasmic reticulum stress and mitochondrial protection. Sci Rep. 2016 Sep 27;6:34091.
  8. Kommaddi RP, Jean-Charles PY, Shenoy SK. Phosphorylation of the deubiquitinase USP20 by protein kinase A regulates post-endocytic trafficking of beta2 adrenergic receptors to autophagosomes during physiological stress. J Biol Chem. 2015 Apr 3;290(14):8888-8903.
  9. Kommaddi RP, Shenoy SK. Arrestins and protein ubiquitination. Prog Mol Biol Transl Sci. 2013;118:175-204. Review.
  10. Han SO, Kommaddi RP, Shenoy SK. Distinct roles for beta-arrestin2 and arrestin-domain-containing proteins in beta2 adrenergic receptor trafficking. EMBO Rep. 2013 Feb;14(2):164-171.
  11. Kommaddi RP, Thomas R, Ceni C, Daigneault K, Barker PA. Trk-dependent ADAM17 activation facilitates neurotrophin survival signaling. FASEB J. 2011 Jun;25(6):2061-70.
  12. Kommaddi RP, Dickson KM, Barker PA. Stress-induced expression of the p75 neurotrophin receptor is regulated by O-GlcNAcylation of the Sp1 transcription factor. J Neurochem. 2011 Feb;116(3):396-405.
  13. Ceni C, Kommaddi RP, Thomas R, Vereker E, Liu X, McPherson PS, Ritter B, Barker PA. The p75NTR intracellular domain generated by neurotrophin-induced receptor cleavage potentiates Trk signaling. J Cell Sci. 2010 Jul 1;123(Pt 13):2299-307.
  14. Agarwal V, Kommaddi RP, Valli K, Ryder D, Hyde TM, Kleinman JE, Strobel HW, Ravindranath V. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite. PLoS One. 2008 Jun 11;3(6):e2337.
  15. Kommaddi RP, Turman CM, Moorthy B, Wang L, Strobel HW, Ravindranath V. An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA-reactive metabolites. J Neurochem. 2007 Aug;102(3):867-877.
  16. Ravindranath V, Kommaddi RP, Pai HV. Unique cytochromes P450 in human brain: implication in disease pathogenesis. Journal of Neural Transmission Suppl. 2006;(70):167-71. Review.
  17. Chinta SJ, Kommaddi RP, Turman CM, Strobel HW, Ravindranath V. Constitutive expression and localization of cytochrome P-450 1A1 in rat and human brain: presence of a splice variant form in human brain. J Neurochem. 2005 May;93(3):724-36.
  18. Pai HV, Kommaddi RP, Chinta SJ, Mori T, Boyd MR, Ravindranath V. A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine. J Biol Chem. 2004 Jun 25;279(26):27383-9.

 

This will be updated soon.

 

 

 

 

Centre for Brain Research
Indian Institute of Science Campus
CV Raman Avenue
Bangalore 560012. India.

Email: reddy@iisc.ac.in
Telephone: Office +91 80 2293 3432