Faculty

faculty-vijayalakshmi

Vijayalakshmi Ravindranath

Professor

Phone : +91 80 2293 3431
E-Mail : viji[at]iisc.ac.in
web : www.cns.iisc.ac.in/viji/

Research Areas

Pathogenic mechanisms underlying neurodegenerative disorders


Research Details

Brain related disorders are known to contribute up to one-third of the total disease burden. Among the brain related disorders, which comprise of both neurological and psychiatric illnesses, a cause of serious concern are the age-related disorders such as senile dementia, Alzheimer’s disease, Parkinson’s disease etc. These disorders are progressive and irreversible, and currently no cure is available since the etiopathogenesis of these disorders are poorly understood. The overall interest of the laboratory is to understand the pathogenic mechanisms underlying these disorders with a goal to develop disease-modifying therapies.

A characteristic feature of many neurodegenerative diseases is region-specific neuronal dysfunction and death. Upon closer inspection, one finds that within the affected brain regions, subpopulations of neurons are selectively vulnerable to degeneration. In Parkinson’s disease (PD), the A9 subgroup of dopaminergic neurons of the substantia nigra (SNpc) and their terminals in the striatum degenerate, while the dopaminergic neurons of the ventral tegmental area (VTA) are unaffected. Our laboratory is interested in understanding the molecular mechanisms involved in this selective vulnerability. We have earlier shown that redox perturbation of protein thiols underlies the mitochondrial complex I dysfunction seen in animal model for Parkinson’s disease. It is our hypothesis that thiol modification occurring as a result of oxidative stress results in mitochondrial dysfunction and altered downstream redox signaling leading to activation of cell death pathways in a region specific manner. We investigate the early events in terms of activation of the cell death pathway and the suppression of the cell survival pathways. Understanding the selective vulnerability would help develop therapeutic strategies that can slow down the progression of the disease. The incidence of PD is lower in women and estrogen is a potent neuroprotector. Our lab investigates the mechanism underlying the neuroprotection afforded by estrogen with a goal towards developing neuroprotective strategies for PD.

   pdg1

MPTP-induced loss of dopaminergic neurons in Substantia nigra pars compacta (SNpc) of midbrain. Tyrosine hydroxylase immunostaining of dopaminergic neurons in the substantia nigra of mice treated with vehicle (A), MPTP for 8 d (B), and 14d (C). Dopaminergic neurons of the ventral tegmental area (VTA) remain unaffected following MPTP treatment. Quantitative stereological analysis of the tyrosine hydroxylase positive neurons’ profile from saline (black bar), 8d (red bar) and 14d (green bar) MPTP treated groups. Values are mean ±SD (n=5). Asterisks indicate values significantly different from respective controls.

Schematic representation of the involvement of ASK1 and Daxx in MPTP mediated toxicity: 1-methyl-4-phenylpyridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes increased production of reactive oxygen species (ROS) and mitochondrial dysfunction in dopaminergic neurons by inhibiting complex I of the electron transport chain. ROS also activate apoptosis signal regulating kinase (ASK1) through the oxidation of thioredoxin (TRX), which helps its dissociation from ASK1. As a consequence, the downstream kinases, MKK4 and Jun N-terminal kinase (JNK) are phosphorylated. Daxx subsequently translocates to the cytosol from the nucleus by dissociating from DJ-1 in the nucleus or through the phosphorylation of Daxx by JNK. The interaction of Daxx and ASK1 in the cytosol ensues the death cascade. Approaches aimed at maintenance of the protein thiol homeostasis through a thiol delivery agent, such as ALA can help terminate this cascade and attenuate MPTP-induced neurodegeneration. DAT – dopamine transporter; LD – lipoamide dehydrogenase; N – nucleus; PML – promyelocytic leukaemia nuclear bodies; ALA – a-lipoic acid; DHLA – dihydrolipoic acid.

pdg2

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a gradual loss of memory followed by deterioration of higher cognitive functions such as language, visuospatial perception, judgement and behavior. The neuropathological features of AD include intracellular tangles and extracellular plaques, which lead to loss of neurons and synaptic integrity in the brain. Traditional systems of medicine such as Ayurveda offer a knowledge base that can be utilized for development of therapeutic intervention strategies for AD. We examine the effect of the medicinal preparations at the behavioural, pathological and molecular levels using transgenic animal models of AD.

ag1

Plaque pathology in wild type and transgenic mouse carrying mutations in amyloid precursor protein and presenilin visualized as beta amyloid containing plaques.

In addition, we have a long-standing interest in understanding drug metabolism in brain, particularly human brain. We have shown that brain-specific forms of the major drug metabolizing enzyme cytochrome P450 exist, which can modify therapeutic action of drugs through biotransformation. P450 enzymes also play a role in regulating inflammatory response and thus have an impact in the pathogenesis and progression of neurodegenerative disorders, which is currently being investigated in animal models of AD.

s1

Localization of CYP4F11 mRNA in cortex (a), midbrain (b), and dentate gyrus of hippocampus (c) using fluorescence in situ hybridization showing constitutive expression of CYP4F11 in human brain.

Funding

  • RO1 grant (MH70054), National Institutes of Health, USA
  • J.C. Bose Fellowship, DST, India

Publications

Ahmad F, Singh K, Das D, Gowaikar R, Shaw E, Ramachandran A, Rupanagudi KV, Kommaddi RP, Bennett DA, Ravindranath V, (2017), ROS-mediated loss of synaptic Akt1 signaling leads to deficient activity-dependent protein translation early in Alzheimer’s disease, Antioxid Redox Signal

Ray A, Kambali M, Ravindranath V, (2016), Thiol Oxidation by Diamide Leads to Dopaminergic Degeneration and Parkinsonism Phenotype in Mice: A Model for Parkinson’s Disease, Antioxid Redox Signal, 10;25(5):, 252-67

Saykally JN, Hatic H, Keeley KL, Jain S, Ravindranath V, (2016), Citron BA: Withaniasomnifera Extract Protects Model Neurons from In Vitro Traumatic Injury, Cell Transplant, doi: 10.3727/096368916X693770

Ray A, Sehgal N, Karunakaran S, Rangarajan G, Ravindranath V, (2015), MPTP activates ASK1-p38 MAPK signaling pathway through TNF-dependent Trx1 oxidation in parkinsonism mouse model, Free Radic Biol Med, 87:312-25

Ravindranath V, Dang HM, Goya RG, Mansour H, Nimgaonkar VL, Russell VA, Xin Y, (2015), Regional research priorities in brain and nervous system disorders, Nature, 527(7578):S198-206

Ahmad F, Nidadavolu P, Durgadoss L, Ravindranath V., (2014), Critical cysteines in Akt1 regulate its activity and proteasomal degradation: implications for neurodegenerative diseases, Free Radic Biol Med, 74:118-28

Ravindranath, V. and Strobel H.W., (2013), Cytochrome P450-mediated metabolism in brain: functional roles and their implications, Expert Opin Drug Metab Toxicol, 9: 551-558

Sehgal N., Gupta, A., Khader Valli, R., Shanker Datt Joshi, Jessica T. Mills, Edith Hamel, Khanna, P., Jain, S. C., Thakur, S.S. and Ravindranath V, (2012), Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver, Proc. Natl. Acad. Sci, USA 109: 3510-5

Saeed U, Ray A, Valli RK, Kumar AM, Ravindranath V, (2010), DJ-1 Loss by Glutaredoxin But Not Glutathione Depletion Triggers Daxx Translocation and Cell Death.Antioxid Redox Signal

Saeed U, Karunakaran S, Meka DP, Koumar RC, Ramakrishnan S, Joshi SD, Nidadavolu P, Ravindranath V., (2009), Redox activated MAP kinase death signaling cascade initiated by ASK1 is not activated in female mice following MPTP: novel mechanism of neuroprotection., Neurotox Res., 16(2):116-26.

Karunakaran S, Ravindranath V., (2009), Activation of p38 MAPK in the substantia nigra leads to nuclear translocation of NF-kappaB in MPTP-treated mice: implication in Parkinson’s disease., J Neurochem. , 109(6):1791-9.