Vidyadhara D J, PhD

Research

The mission of my lab is to unravel the mechanisms of synaptic degeneration in Parkinson’s disease and aging, and leverage this knowledge to bring meaningful relief to those affected! 

Neurodegenerative processes in Parkinson's disease (PD) arise from an interplay between aging and genetic/environmental factors. The primary sites of degeneration are dopamine-producing neurons in the nigrostriatal network of the brain. While it is established that synapses of these neurons degenerate before the cell bodies, the mechanisms behind this synaptic degeneration and its role in the overall disease process remain unclear. Our lab aims to address this gap by studying novel PD-related mutations in presynaptic endolysosomal proteins, examining how these mutations interact with genetic and environmental risk factors, as well as aging.

My team is pursuing this goal through three comprehensive studies that integrate mechanistic investigations using mouse models, patient-derived and CRISPRed iPSC neurons, SH-SY5Y cell lines, and patient biospecimens. In our first study, we are investigating how presynaptic endolysosomal dysfunction leads to PD. Specifically, we are focusing on presynaptic endocytosis, synaptic vesicle recycling, and presynaptic autophagy. We are using PD-related gene mutations that directly affect these pathways to establish this connection. In the second study, we are investigating the impact of genetic and environmental risk factors for PD on presynaptic endocytosis, to determine whether these factors act through or in conjunction with defective presynaptic endocytosis to cause PD. In the third study, we aim to delineate the effect of aging on the presynaptic endolysosomal system in different neuronal types, to assess whether it plays a role in the differential susceptibility of neuronal types to age-related neurodegeneration.

We are employing a diverse range of advanced techniques in histopathology, microscopy, biochemistry, subcellular proteomics, mouse behavior, viral gene manipulations, and various cell biology methods. Additionally, we have established collaboration for electrophysiological studies and to utilize C. elegans models to further investigate our research questions, while also partnering with clinicians to translate our findings to benefit those affected. We are committed to pursuing our research in an inclusive laboratory environment that embraces diverse people and perspectives.

Training and Education

Postdoctoral Associate and Associate Research Scientist, 2018-2024 
Dept. of Neuroscience and Neurology, Yale University School of Medicine, New Haven, CT

PhD in Neuroscience/Neurophysiology, 2012-2018 
National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India

M.Sc. in Medical Physiology, 2007-2011 
Kasturba Medical College, Manipal University (MAHE), Manipal, India

B.Sc. in Biochemistry, Microbiology & Biotechnology, 2004-2007
University of Mysore, Mysore, India

Research Support (Completed)

• Michael J. Fox Foundation, Target Advancement Program Grant, Aug. 2021 – 2023
  "Pathogenic Mechanisms for Auxilin-mediated Parkinson’s Disease"
  No. MJFF-020160, $150,000, Role: Co-Principal Investigator
• U.S. Dept. of Defense, CDMRP Early Investigator Research Award, July 2019 - 2022
  "Role of Lipid Dyshomeostasis in Cognitive Dysfunction of Parkinson's Disease"
  No. W81XWH-19-1-0264, $339,746, Role: Principal Investigator
• NIMHANS, Bangalore, India, Institute Fellowship (All India 2nd rank), May 2012 - 2017
  INR 1,260,000, Role: PhD Scholar 

Publications

• DJ Vidyadhara, David Bäckström, Risha Chakraborty, Jiapeng Ruan, Jae-Min Park, Pramod K. Mistry, Sreeganga. S. Chandra. Synaptic vesicle endocytosis deficits underlie GBA-linked cognitive dysfunction in Parkinson’s disease and Dementia with Lewy bodies. bioRxiv, 2024, https://doi.org/10.1101/2024.10.23.619548 
• DJ Vidyadhara, M. Somayaji, N. Wade, B. Yucel, H. Zhao…., Dalibor Sames, Lois Greene, David Sulzer, and Sreganga S. Chandra. Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease. Cell Reports, 2023, https://doi.org/10.1016/j.celrep.2023.112231
• Xi Cheng, Yu Tang, DJ Vidyadhara, Ben-Zheng Li, M. Zimmerman, A Pak, A Klug, SS Chandra, A Chubykin. Impaired Presynaptic Plasticity, Visual Mismatch Negativity, and Familiarity-Evoked Oscillations in Auxilin Knockout Mice, Cell iScience, 2023, https://doi.org/10.1016/j.isci.2023.107842
• EM Lopez, DJ Vidyadhara, T Liberia, SJ. M, LE. Harmon, RM. Hsu, K Han, B Yücel, SS Chandra, CA Greer. α-Synuclein pathology and reduced neurogenesis in the olfactory system affect olfaction in a mouse model of Parkinson’s disease. Journal of Neuroscience, 2023, https://doi.org/10.1523/JNEUROSCI.1526-22.2022
• Yarreiphang H, DJ Vidyadhara, AN Nambi, Raju TR, C Sagar, Alladi PA. Apoptotic factors and mitochondrial complexes assist determination of strain-specific susceptibility of mice to Parkinsonian neurotoxin MPTP. Molecular Neurobiology, 2023, https://link.springer.com/article/10.1007/s12035-023-03372-1
• S. Massaro Tieze, SS. Chandra, DJ Vidyadhara. Subcellular Fractionation for the Isolation of Synaptic Components from the Murine Brain, J. of Visualized Experiments (JoVE), 2022, https://dx.doi.org/10.3791/64574
• Michael C, H Bock, I Serrano, B Bechand, DJ Vidyadhara…… SS Chandra, J McCorvy, D Sames. Pharmacological mechanism of the non-Hallucinogenic 5-HT2A agonist Ariadne and analogs, ACS Chemical Neuroscience, 2022, https://doi.org/10.1021/acschemneuro.2c00597
• CS Boddupalli, S Nair, G Belinsky, J Gans, E Teeple, T Nguyen, S Mehta, L Guo, M Kramer, J Ruan, M Davison, DJ Vidyadhara, B Zhang, K Klinger, Pramod Mistry. Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells. eLife, 2022, https://doi.org/10.7554/eLife.79830
• DJ Vidyadhara, Yarreiphang H, Raju TR, Alladi PA. Differences in neuronal numbers, morphology and developmental apoptosis in mice nigra provide experimental evidence of ontogenic origin of vulnerability to Parkinson's disease. Neurotoxicity Research, 2021, https://doi.org/10.1007/s12640-021-00439-6
• SN Suresh, J Pandurangi, R Murumalla, DJ Vidyadhara, L Garimella, A Acharya, S Rai, A Paul, H Yarreiphang, M S Pillai, M Giridharan, JP Clement, PA Alladi, T Saiyed, R Manjithaya,  Small molecule modulator of aggrephagy regulates neuroinflammation to curb pathogenesis of neurodegeneration, The Lancet EBioMedicine, 2019, https://doi.org/10.1016/j.ebiom.2019.10.036
• DJ Vidyadhara, A Sasidharan, BM Kutty, TR Raju, PA Alladi. Admixing MPTP-resistant and MPTP-vulnerable mice enhances striatal field potentials and calbindin-D28K expression to avert motor behaviour deficits, Behavioural brain research, 2019, https://doi.org/10.1016/j.bbr.2018.12.015
• DJ Vidyadhara, JE Lee, SS Chandra. Role of the endolysosomal system in Parkinson’s disease, Journal of neurochemistry, 2019, https://doi.org/10.1111/jnc.14820
• Ravi M, Senthilkumar S, Popa-Wagner A, P U, Ram K, Guruprasad KP, DJ Vidyadhara. Pluchea lanceolata protects hippocampal neurons from endothelin-1 induced ischemic injury to ameliorate cognitive deficits. J. of Chemical Neuroanatomy, 2018, https://doi.org/10.1016/j.jchemneu.2018.09.002
• Suresh SN, Aravinda C, Malini P, Veena A, DJ Vidyadhara, H Yarreiphang, Shashank Rai, Abhik Paul, James P Clement, Alladi PA, Ravi. M. Modulation of autophagy by a small molecule inverse agonist of ERRα is neuroprotective. Frontiers in Molecular Neuroscience, 2018, https://doi.org/10.3389/fnmol.2018.00109
• Ravi M, Senthilkumar S, Padmaja U, DJ Vidyadhara, Suchitra P, Basavaiah R. Neuroprotective functions of Alpinia galanga in forebrain ischemia induced neuronal damage and oxidative insults in rat hippocampus, Indian Journal of Pharmaceutical Education and Research, 2018, https://doi.org/10.5530/ijper.52.4s.79
• DJ Vidyadhara, Yarre. H, Raju TR, Alladi PA. Admixing of MPTP-Resistant and Susceptible Mice Strains Augments Nigrostriatal Neuronal Correlates to Resist MPTP-Induced Neurodegeneration. Molecular Neurobiology, 2017, https://doi.org/10.1007/s12035-016-0158-y
• Suresh S.N., Aravinda C, Vidyadhara DJ, Yarrei H, ……, Ravi. M. A novel autophagy modulator 6-Bio ameliorates SNCA/α-synuclein toxicity. Autophagy, 2017, https://doi.org/10.1080/15548627.2017.1302045
• G Sivakumar, DJ Vidyadhara, KN Shivananda, T Rajesh, K G Mohandas Rao, Kiranmai S Rai. Prophylactic choline supplementation attenuates vascular cognitive impairment in rodent model of ischemic stroke. Indian Journal of Physiology & Pharmacology, 2017, http://ijpp.com/IJPP%20archives/2017_61_3/246-255.pdf
• DJ Vidyadhara, Yarreiphang H, Abhilash PL, Raju TR, Alladi PA.. Role of nigral dopaminergic neuronal calbindin in determining the differential susceptibility of mice strains to MPTP. J. of Chem. Neuroanatomy, 2016, https://doi.org/10.1016/j.jchemneu.2016.01.001
• Jyothi HJ, Vidyadhara DJ, Anita M, M Philip, Suresh K, G Manoh, Shankar SK, Raju TR, Alladi PA. Aging causes morphological alterations in astrocytes and microglia in human substantia nigra pars compacta. Neurobiology of Aging, 2015, https://doi.org/10.1016/j.neurobiolaging.2015.08.024
• G Sivakumar, DJ Vidyadhara, S Reddy, T Rajesh, R Babu, Mohandas Rao, Kiranmai S Rai. Prophylactic combined supplementation of choline and docosahexaenoic acid attenuates vascular cognitive impairment and preserves hippocampal cell viability in a rat model of chronic cerebral hypoperfusion ischemic brain injury, Int. Jou. of Basic & Clinical Pharmacology, 2015, https://www.ijbcp.com/index.php/ijbcp/article/view/784