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Honors & Awards

  • Best Post-Doctoral Research Fast-Pitch Award, Oregon Health & Science University, Oregon (2018)
  • Runner-up Research Fast-Pitch, Oregon Biosciences Showcase, Oregon (2017)
  • Post-Doctoral Research Fellowship, American Parkinson's Disease Association (APDA) (2016)
  • Graduate Travel Award, Neuromuscular Plasticity Symposium, University of Florida (2013)
  • McKnight Brain Institute Travel Award, McKnight Brain Institute, University of Florida (2013)
  • Outstanding International Student Award, University of Florida (2013)
  • Travel Award, North Central Florida Chapter of Society for Neuroscience (2013)
  • Bryan Robinson Endowment Award, Tallahassee Memorial Neuroscience Center, Florida (2012)
  • Medical Guild Research Incentive Award, University of Florida (2011)
  • Outstanding International Student Achievement, University of Florida (2010)

Boards, Advisory Committees, Professional Organizations

  • Member, The Biochemical Society (2020 - Present)
  • Review Editor, Frontiers, Aging Neuroscience (2020 - Present)
  • Review Editor, The Neuroscientist (2020 - Present)
  • Review Editor, Editorial board of Molecular Diagnostics, a specialty of Frontiers in Molecular Biosciences (2015 - 2018)
  • Member, Society for Neuroscience (2014 - Present)
  • President, The Biotech Society, Hislop School of Biotechnology (2007 - 2008)
  • Member, The Biotech Society, Hislop School of Biotechnology (2006 - 2008)

Stanford Advisors

Research & Scholarship

Current Research and Scholarly Interests

My long-term research interests involve understanding the molecular mechanisms of age-dependent neurodegenerative diseases. My academic and research training were focused in protein misfolding, aging and proteostasis. The focus of my postdoctoral research at Stanford University is understanding the molecular pathobiology of Parkinson?s disease, specifically related to mutations in the LRRK2 gene. My main projects include:
1) Exploring the role of endolysosomal proteins in LRRK2-related PD pathogenesis, especially the malfunctions in disease conditions.
2) Understanding the molecular crosstalks participating in the cognitive impairment associated with Parkinson's and Alzheimer's Disease
3) Developing a reliable imaging technique for analyses of post-mortem brain tissues from Parkinson's Disease patients, which would be key in revealing new molecular pathways and therapeutic opportunities.


All Publications

  • Genetic and Environmental Factors Influence the Pleomorphy of LRRK2 Parkinsonism. International journal of molecular sciences Chittoor-Vinod, V. G., Nichols, R. J., Schule, B. 2021; 22 (3)


    Missense mutations in the LRRK2 gene were first identified as a pathogenic cause of Parkinson's disease (PD) in 2004. Soon thereafter, a founder mutation in LRRK2, p.G2019S (rs34637584), was described, and it is now estimated that there are approximately 100,000 people worldwide carrying this risk variant. While the clinical presentation of LRRK2 parkinsonism has been largely indistinguishable from sporadic PD, disease penetrance and age at onset can be quite variable. In addition, its neuropathological features span a wide range from nigrostriatal loss with Lewy body pathology, lack thereof, or atypical neuropathology, including a large proportion of cases with concomitant Alzheimer's pathology, hailing LRRK2 parkinsonism as the "Rosetta stone" of parkinsonian disorders, which provides clues to an understanding of the different neuropathological trajectories. These differences may result from interactions between the LRRK2 mutant protein and other proteins or environmental factors that modify LRRK2 function and, thereby, influence pathobiology. This review explores how potential genetic and biochemical modifiers of LRRK2 function may contribute to the onset and clinical presentation of LRRK2 parkinsonism. We review which genetic modifiers of LRRK2 influence clinical symptoms, age at onset, and penetrance, what LRRK2 mutations are associated with pleomorphic LRRK2 neuropathology, and which environmental modifiers can augment LRRK2 mutant pathophysiology. Understanding how LRRK2 function is influenced and modulated by other interactors and environmental factors-either increasing toxicity or providing resilience-will inform targeted therapeutic development in the years to come. This will allow the development of disease-modifying therapies for PD- and LRRK2-related neurodegeneration.

    View details for DOI 10.3390/ijms22031045

    View details for PubMedID 33494262

  • Dietary Amino Acids Impact LRRK2-Induced Neurodegeneration in Parkinson's Disease Models. The Journal of neuroscience : the official journal of the Society for Neuroscience Chittoor-Vinod, V. G., Villalobos-Cantor, S. n., Roshak, H. n., Shea, K. n., Abalde-Atristain, L. n., Martin, I. n. 2020; 40 (32): 6234?49


    The G2019S mutation in leucine-rich repeat kinase 2 (LRRK2) is a common cause of Parkinson's disease (PD) and results in age-related dopamine neuron loss and locomotor dysfunction in Drosophila melanogaster through an aberrant increase in bulk neuronal protein synthesis. Under nonpathologic conditions, protein synthesis is tightly controlled by metabolic regulation. Whether nutritional and metabolic influences on protein synthesis can modulate the pathogenic effect of LRRK2 on protein synthesis and thereby impact neuronal loss is a key unresolved question. Here, we show that LRRK2 G2019S-induced neurodegeneration is critically dependent on dietary amino acid content in Drosophila studies with both sexes. Low dietary amino acid concentration prevents aberrant protein synthesis and blocks LRRK2 G2019S-mediated neurodegeneration in Drosophila and rat primary neurons. Unexpectedly, a moderately high-amino acid diet also blocks dopamine neuron loss and motor deficits in Drosophila through a separate mechanism involving stress-responsive activation of 5'-AMP-activated protein kinase (AMPK) and neuroprotective induction of autophagy, implicating the importance of protein homeostasis to neuronal viability. At the highest amino acid diet of the range tested, PD-related neurodegeneration occurs in an age-related manner, but is also observed in control strains, suggesting that it is independent of mutant LRRK2 expression. We propose that dietary influences on protein synthesis and autophagy are critical determinants of LRRK2 neurodegeneration, opening up possibilities for future therapeutic intervention.SIGNIFICANCE STATEMENT Parkinson's disease (PD) prevalence is projected to rise as populations continue to age, yet there are no current therapeutic approaches that delay or stop disease progression. A broad role for leucine-rich repeat kinase 2 (LRRK2) mutations in familial and idiopathic PD has emerged. Here, we show that dietary amino acids are important determinants of neurodegeneration in a Drosophila model of LRRK2 PD. Restricting all amino acids effectively suppresses dopaminergic neuron loss and locomotor deficits and is associated with reduced protein synthesis, while moderately high amino acids similarly attenuate these PD-related phenotypes through a stress-responsive induction of 5'-AMP-activated protein kinase and autophagy. These studies suggest that diet plays an important role in the development of PD-related phenotypes linked to LRRK2.

    View details for DOI 10.1523/JNEUROSCI.2809-19.2020

    View details for PubMedID 32605938

    View details for PubMedCentralID PMC7406281

  • HSP90 Inhibitor, NVP-AUY922, Improves Myelination in Vitro and Supports the Maintenance of Myelinated Axons in Neuropathic Mice. ACS chemical neuroscience Chittoor-Vinod, V. G., Bazick, H. n., Todd, A. G., Falk, D. n., Morelli, K. H., Burgess, R. W., Foster, T. C., Notterpek, L. n. 2019; 10 (6): 2890?2902


    Hereditary demyelinating neuropathies linked to peripheral myelin protein 22 (PMP22) involve the disruption of normal protein trafficking and are therefore relevant targets for chaperone therapy. Using a small molecule HSP90 inhibitor, EC137, in cell culture models, we previously validated the chaperone pathway as a viable target for therapy development. Here, we tested five commercially available inhibitors of HSP90 and identified BIIB021 and AUY922 to support Schwann cell viability and enhance chaperone expression. AUY922 showed higher efficacy, compared to BIIB021, in enhancing myelin synthesis in dorsal root ganglion explant cultures from neuropathic mice. For in vivo testing, we randomly assigned 2-3 month old C22 and 6 week old Trembler J (TrJ) mice to receive two weekly injections of either vehicle or AUY922 (2 mg/kg). By the intraperitoneal (i.p.) route, the drug was well-tolerated by all mice over the 5 month long study, without influence on body weight or general grooming behavior. AUY922 improved the maintenance of myelinated nerves of both neuropathic models and attenuated the decline in rotarod performance and peak muscle force production in C22 mice. These studies highlight the significance of proteostasis in neuromuscular function and further validate the HSP90 pathway as a therapeutic target for hereditary neuropathies.

    View details for DOI 10.1021/acschemneuro.9b00105

    View details for PubMedID 31017387

    View details for PubMedCentralID PMC6588339

  • Genetic Modifiers of Neurodegeneration in a Drosophila Model of Parkinson's Disease. Genetics Lavoy, S. n., Chittoor-Vinod, V. G., Chow, C. Y., Martin, I. n. 2018; 209 (4): 1345?56


    Disease phenotypes can be highly variable among individuals with the same pathogenic mutation. There is increasing evidence that background genetic variation is a strong driver of disease variability in addition to the influence of environment. To understand the genotype-phenotype relationship that determines the expressivity of a pathogenic mutation, a large number of backgrounds must be studied. This can be efficiently achieved using model organism collections such as the Drosophila Genetic Reference Panel (DGRP). Here, we used the DGRP to assess the variability of locomotor dysfunction in a LRRK2 G2019S Drosophila melanogaster model of Parkinson's disease (PD). We find substantial variability in the LRRK2 G2019S locomotor phenotype in different DGRP backgrounds. A genome-wide association study for candidate genetic modifiers reveals 177 genes that drive wide phenotypic variation, including 19 top association genes. Genes involved in the outgrowth and regulation of neuronal projections are enriched in these candidate modifiers. RNAi functional testing of the top association and neuronal projection-related genes reveals that pros, pbl, ct, and CG33506 significantly modify age-related dopamine neuron loss and associated locomotor dysfunction in the Drosophila LRRK2 G2019S model. These results demonstrate how natural genetic variation can be used as a powerful tool to identify genes that modify disease-related phenotypes. We report novel candidate modifier genes for LRRK2 G2019S that may be used to interrogate the link between LRRK2, neurite regulation and neuronal degeneration in PD.

    View details for DOI 10.1534/genetics.118.301119

    View details for PubMedID 29907646

    View details for PubMedCentralID PMC6063243

  • Elevated Peripheral Myelin Protein 22, Reduced Mitotic Potential, and Proteasome Impairment in Dermal Fibroblasts from Charcot-Marie-Tooth Disease Type 1A Patients. The American journal of pathology Lee, S. n., Bazick, H. n., Chittoor-Vinod, V. n., Al Salihi, M. O., Xia, G. n., Notterpek, L. n. 2018; 188 (3): 728?38


    A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. Because PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non-neuropathic individuals were used as controls. CMT1A patient-derived cultures contain approximately 1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II and LAMP1. These results indicate that the abnormalities in the subcellular processing of excess PMP22 elicit a detectable response in human CMT1A fibroblasts, a phenotype that resembles Schwann cells from neuropathic mice. These findings support the use of human CMT1A fibroblasts as a platform for therapy testing.

    View details for DOI 10.1016/j.ajpath.2017.10.021

    View details for PubMedID 29246495

    View details for PubMedCentralID PMC5842032

  • Parkinson disease: Insect screens for PD therapies - keep the flies in. Nature reviews. Neurology Martin, I. n., Chittoor, V. G. 2016; 12 (6): 318?19

    View details for DOI 10.1038/nrneurol.2016.56

    View details for PubMedID 27125634

  • Inducible HSP70 is critical in preventing the aggregation and enhancing the processing of PMP22. ASN neuro Chittoor-Vinod, V. G., Lee, S. n., Judge, S. M., Notterpek, L. n. 2015; 7 (1)


    Chaperones, also called heat shock proteins (HSPs), transiently interact with proteins to aid their folding, trafficking, and degradation, thereby directly influencing the transport of newly synthesized molecules. Induction of chaperones provides a potential therapeutic approach for protein misfolding disorders, such as peripheral myelin protein 22 (PMP22)-associated peripheral neuropathies. Cytosolic aggregates of PMP22, linked with a demyelinating Schwann cell phenotype, result in suppression of proteasome activity and activation of proteostatic mechanisms, including the heat shock pathway. Although the beneficial effects of chaperones in preventing the aggregation and improving the trafficking of PMP22 have been repeatedly observed, the requirement for HSP70 in events remains elusive. In this study, we show that activation of the chaperone pathway in fibroblasts from PMP22 duplication-associated Charcot-Marie-Tooth disease type 1A patient with an FDA-approved small molecule increases HSP70 expression and attenuates proteasome dysfunction. Using cells from an HSP70.1/3(-/-) (inducible HSP70) mouse model, we demonstrate that under proteotoxic stress, this chaperone is critical in preventing the aggregation of PMP22, and this effect is aided by macroautophagy. When examined at steady-state, HSP70 appears to play a minor role in the trafficking of wild-type-PMP22, while it is crucial for preventing the buildup of the aggregation-prone Trembler-J-PMP22. HSP70 aids the processing of Trembler-J-PMP22 through the Golgi and its delivery to lysosomes via Rab7-positive vesicles. Together, these results demonstrate a key role for inducible HSP70 in aiding the processing and hindering the accumulation of misfolded PMP22, which in turn alleviates proteotoxicity within the cells.

    View details for DOI 10.1177/1759091415569909

    View details for PubMedID 25694550

    View details for PubMedCentralID PMC4342366

  • Biochemical characterization of protein quality control mechanisms during disease progression in the C22 mouse model of CMT1A. ASN neuro Chittoor, V. G., Sooyeon, L. n., Rangaraju, S. n., Nicks, J. R., Schmidt, J. T., Madorsky, I. n., Narvaez, D. C., Notterpek, L. n. 2013; 5 (5): e00128


    Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary demyelinating neuropathy linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Transgenic C22 mice, a model of CMT1A, display many features of the human disease, including slowed nerve conduction velocity and demyelination of peripheral nerves. How overproduction of PMP22 leads to compromised myelin and axonal pathology is not fully understood, but likely involves subcellular alterations in protein homoeostatic mechanisms within affected Schwann cells. The subcellular response to abnormally localized PMP22 includes the recruitment of the ubiquitin-proteasome system (UPS), autophagosomes and heat-shock proteins (HSPs). Here we assessed biochemical markers of these protein homoeostatic pathways in nerves from PMP22-overexpressing neuropathic mice between the ages of 2 and 12 months to ascertain their potential contribution to disease progression. In nerves of 3-week-old mice, using endoglycosidases and Western blotting, we found altered processing of the exogenous human PMP22, an abnormality that becomes more prevalent with age. Along with the ongoing accrual of misfolded PMP22, the activity of the proteasome becomes compromised and proteins required for autophagy induction and lysosome biogenesis are up-regulated. Moreover, cytosolic chaperones are consistently elevated in nerves from neuropathic mice, with the most prominent change in HSP70. The gradual alterations in protein homoeostatic response are accompanied by Schwann cell de-differentiation and macrophage infiltration. Together, these results show that while subcellular protein quality control mechanisms respond appropriately to the presence of the overproduced PMP22, with aging they are unable to prevent the accrual of misfolded proteins.

    View details for DOI 10.1042/AN20130024

    View details for PubMedID 24175617

    View details for PubMedCentralID PMC3848555

  • The palmitoylation state of PMP22 modulates epithelial cell morphology and migration. ASN neuro Zoltewicz, S. J., Lee, S. n., Chittoor, V. G., Freeland, S. M., Rangaraju, S. n., Zacharias, D. A., Notterpek, L. n. 2012; 4 (6): 409?21


    PMP22 (peripheral myelin protein 22), also known as GAS 3 (growth-arrest-specific protein 3), is a disease-linked tetraspan glycoprotein of peripheral nerve myelin and constituent of intercellular junctions in epithelia. To date, our knowledge of the post-translational modification of PMP22 is limited. Using the CSS-Palm 2.0 software we predicted that C85 (cysteine 85), a highly conserved amino acid located between the second and third transmembrane domains, is a potential site for palmitoylation. To test this, we mutated C85S (C85 to serine) and established stable cells lines expressing the WT (wild-type) or the C85S-PMP22. In Schwann and MDCK (Madin-Darby canine kidney) cells mutating C85 blocked the palmitoylation of PMP22, which we monitored using 17-ODYA (17-octadecynoic acid). While palmitoylation was not necessary for processing the newly synthesized PMP22 through the secretory pathway, overexpression of C85S-PMP22 led to pronounced cell spreading and uneven monolayer thinning. To further investigate the functional significance of palmitoylated PMP22, we evaluated MDCK cell migration in a wound-healing assay. While WT-PMP22 expressing cells were resistant to migration, C85S cells displayed lamellipodial protrusions and migrated at a similar rate to vector control. These findings indicate that palmitoylation of PMP22 at C85 is critical for the role of the protein in modulating epithelial cell shape and motility.

    View details for DOI 10.1042/AN20120045

    View details for PubMedID 23127255

    View details for PubMedCentralID PMC3563111

  • Synthesis, gene silencing, and molecular modeling studies of 4'-C-aminomethyl-2'-O-methyl modified small interfering RNAs. The Journal of organic chemistry Gore, K. R., Nawale, G. N., Harikrishna, S. n., Chittoor, V. G., Pandey, S. K., H÷bartner, C. n., Patankar, S. n., Pradeepkumar, P. I. 2012; 77 (7): 3233?45


    The linear syntheses of 4'-C-aminomethyl-2'-O-methyl uridine and cytidine nucleoside phosphoramidites were achieved using glucose as the starting material. The modified RNA building blocks were incorporated into small interfering RNAs (siRNAs) by employing solid phase RNA synthesis. Thermal melting studies showed that the modified siRNA duplexes exhibited slightly lower T(m) (?1 ░C/modification) compared to the unmodified duplex. Molecular dynamics simulations revealed that the 4'-C-aminomethyl-2'-O-methyl modified nucleotides adopt South-type conformation in a siRNA duplex, thereby altering the stacking and hydrogen-bonding interactions. These modified siRNAs were also evaluated for their gene silencing efficiency in HeLa cells using a luciferase-based reporter assay. The results indicate that the modifications are well tolerated in various positions of the passenger strand and at the 3' end of the guide strand but are less tolerated in the seed region of the guide strand. The modified siRNAs exhibited prolonged stability in human serum compared to unmodified siRNA. This work has implications for the use of 4'-C-aminomethyl-2'-O-methyl modified nucleotides to overcome some of the challenges associated with the therapeutic utilities of siRNAs.

    View details for DOI 10.1021/jo202666m

    View details for PubMedID 22372696

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