Bio

Honors & Awards


  • DAAD Travel fellowship, Cyceron, University of Caen, Caen, France (2013)
  • Travel Award - ISTH 2013, University of Giessen (2013)
  • DAAD Travel fellowship, Theodor Kocher Institute, Bern, Switzerland (2013)
  • DAAD STIBET teaching assistantship, Courses in Bioinformatics - University of Giessen (2010-2013)

Professional Education


  • Doctor of Philosophy, Justus-Liebig-Universität Gießen, Biochemistry, Neuroscience (2014)
  • Master of Science, University of Abertay Dundee, Biotechnology (2006)
  • Bachelor of Science, University of Pune, Microbiology, Chemistry, Zoology (2005)

Stanford Advisors


Publications

All Publications


  • Potential biomarkers to follow the progression and treatment response of Huntington's disease. journal of experimental medicine Disatnik, M., Joshi, A. U., Saw, N. L., Shamloo, M., Leavitt, B. R., Qi, X., Mochly-Rosen, D. 2016

    Abstract

    Huntington's disease (HD) is a rare genetic disease caused by expanded polyglutamine repeats in the huntingtin protein resulting in selective neuronal loss. Although genetic testing readily identifies those who will be affected, current pharmacological treatments do not prevent or slow down disease progression. A major challenge is the slow clinical progression and the inability to biopsy the affected tissue, the brain, making it difficult to design short and effective proof of concept clinical trials to assess treatment benefit. In this study, we focus on identifying peripheral biomarkers that correlate with the progression of the disease and treatment benefit. We recently developed an inhibitor of pathological mitochondrial fragmentation, P110, to inhibit neurotoxicity in HD. Changes in levels of mitochondrial DNA (mtDNA) and inflammation markers in plasma, a product of DNA oxidation in urine, mutant huntingtin aggregates, and 4-hydroxynonenal adducts in muscle and skin tissues were all noted in HD R6/2 mice relative to wild-type mice. Importantly, P110 treatment effectively reduced the levels of these biomarkers. Finally, abnormal levels of mtDNA were also found in plasma of HD patients relative to control subjects. Therefore, we identified several potential peripheral biomarkers as candidates to assess HD progression and the benefit of intervention for future clinical trials.

    View details for PubMedID 27821553

  • The entangled ER-mitochondrial axis as a potential therapeutic strategy in neurodegeneration: A tangled duo unchained. Cell calcium Joshi, A. U., Kornfeld, O. S., Mochly-Rosen, D. 2016; 60 (3): 218-234

    Abstract

    Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca(2+) transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases.

    View details for DOI 10.1016/j.ceca.2016.04.010

    View details for PubMedID 27212603

  • Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Protein-Protein Interaction Inhibitor Reveals a Non-catalytic Role for GAPDH Oligomerization in Cell Death JOURNAL OF BIOLOGICAL CHEMISTRY Qvit, N., Joshi, A. U., Cunningham, A. D., Ferreira, J. C., Mochly-Rosen, D. 2016; 291 (26): 13608-13621

    Abstract

    Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), an important glycolytic enzyme, has a non-catalytic (thus a non-canonical) role in inducing mitochondrial elimination under oxidative stress. We recently demonstrated that phosphorylation of GAPDH by delta protein kinase C (PKC) inhibits this GAPDH-dependent mitochondrial elimination. deltaPKC phosphorylation of GAPDH correlates with increased cell injury following oxidative stress, suggesting that inhibiting GAPDH phosphorylation should decrease cell injury. Using rational design, we identified pseudoGAPDH peptide, an inhibitor of deltaPKC-mediated GAPDH phosphorylation that does not inhibit the phosphorylation of other deltaPKC substrates. Unexpectedly, pseudoGAPDH decreased mitochondrial elimination and increased cardiac damage in an animal model of heart attack. Either treatment with pseudoGAPDH or direct phosphorylation of GAPDH by deltaPKC decreased GAPDH tetramerization, which corresponded to reduced GAPDH glycolytic activity in vitro and ex vivo. Taken together, our study identified the potential mechanism by which oxidative stress inhibits the protective GAPDH-mediated elimination of damaged mitochondria. Our study also identified a pharmacological tool, pseudoGAPDH peptide, with interesting properties. pseudoGAPDH peptide is an inhibitor of the interaction between deltaPKC and GAPDH, and of the resulting phosphorylation of GAPDH by deltaPKC. pseudoGAPDH peptide is also an inhibitor of GAPDH oligomerization and thus an inhibitor of GAPDH glycolytic activity. Finally, we found that pseudoGAPDH peptide is an inhibitor of the elimination of damaged mitochondria. We discuss how this unique property of increasing cell damage following oxidative stress suggests a potential use for pseudoGAPDH peptide-based therapy.

    View details for DOI 10.1074/jbc.M115.711630

    View details for Web of Science ID 000379771100018

    View details for PubMedID 27129213

  • Deficiency of Factor VII activating protease alters the outcome of ischemic stroke in mice EUROPEAN JOURNAL OF NEUROSCIENCE Joshi, A. U., Orset, C., Engelhardt, B., Baumgart-Vogt, E., Gerriets, T., Vivien, D., Kanse, S. M. 2015; 41 (7): 963-973

    View details for DOI 10.1111/ejn.12830

    View details for Web of Science ID 000352540800010

  • Murine aldo-keto reductase family 1 subfamily B: identification of AKR1B8 as an ortholog of human AKR1B10. Biological chemistry Joshi, A., Rajput, S., Wang, C., Ma, J., Cao, D. 2010; 391 (12): 1371-8

    Abstract

    Aldo-keto reductase family 1 member B10 (AKR1B10), over-expressed in multiple human cancers, might be implicated in cancer development and progression via detoxifying cytotoxic carbonyls and regulating fatty acid synthesis. In the present study, we investigated the ortholog of AKR1B10 in mice, an ideal modeling organism greatly contributing to human disease investigations. In the mouse, there are three aldo-keto reductase family 1 subfamily B (AKR1B) members, i.e., AKR1B3, AKR1B7, and AKR1B8. Among them, AKR1B8 has the highest similarity to human AKR1B10 in terms of amino acid sequence, computer-modeled structures, substrate spectra and specificity, and tissue distribution. More importantly, similar to human AKR1B10, mouse AKR1B8 associates with murine acetyl-CoA carboxylase-? and mediates fatty acid synthesis in colon cancer cells. Taken together, our data suggest that murine AKR1B8 is the ortholog of human AKR1B10.

    View details for DOI 10.1515/BC.2010.144

    View details for PubMedID 21087085

  • VCP recruitment to mitochondria causes mitophagy impairment and neurodegeneration in models of Huntington's disease. Nature communications Guo, X., Sun, X., Hu, D., Wang, Y., Fujioka, H., Vyas, R., Chakrapani, S., Joshi, A. U., Luo, Y., Mochly-Rosen, D., Qi, X. 2016; 7: 12646-?

    Abstract

    Mutant Huntingtin (mtHtt) causes neurodegeneration in Huntington's disease (HD) by evoking defects in the mitochondria, but the underlying mechanisms remains elusive. Our proteomic analysis identifies valosin-containing protein (VCP) as an mtHtt-binding protein on the mitochondria. Here we show that VCP is selectively translocated to the mitochondria, where it is bound to mtHtt in various HD models. Mitochondria-accumulated VCP elicits excessive mitophagy, causing neuronal cell death. Blocking mtHtt/VCP mitochondrial interaction with a peptide, HV-3, abolishes VCP translocation to the mitochondria, corrects excessive mitophagy and reduces cell death in HD mouse- and patient-derived cells and HD transgenic mouse brains. Treatment with HV-3 reduces behavioural and neuropathological phenotypes of HD in both fragment- and full-length mtHtt transgenic mice. Our findings demonstrate a causal role of mtHtt-induced VCP mitochondrial accumulation in HD pathogenesis and suggest that the peptide HV-3 might be a useful tool for developing new therapeutics to treat HD.

    View details for DOI 10.1038/ncomms12646

    View details for PubMedID 27561680

  • Plasma factor VII-activating protease antigen levels and activity are increased in ischemic stroke. Journal of thrombosis and haemostasis : JTH Hanson, E., Kanse, S. M., Joshi, A., Jood, K., Nilsson, S., Blomstrand, C., Jern, C. 2012; 10 (5): 848-56

    Abstract

    Factor VII-activating protease (FSAP) is a recently discovered plasma protease with a role in the regulation of hemostasis and vascular remodeling processes. Higher levels and activity of FSAP have been reported in patients with deep vein thrombosis, but there are no data on plasma FSAP in ischemic stroke (IS).To investigate whether FSAP antigen levels and activity are associated with IS and/or etiologic subtypes of IS.To assess the potential association between FSAP and IS, plasma FSAP antigen levels and activity were measured in 600 consecutive IS patients and 600 population-based controls from the case-control study the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). Blood sampling was performed in the acute phase and 3 months after the index stroke. FSAP was also investigated at the genetic level by genotyping of 33 single-nucleotide polymorphisms.Increased FSAP antigen level and activity, at both time-points, were independently associated with IS. Subtype analysis revealed similar associations for both FSAP measures, at both time-points, in all main IS subtypes. FSAP genotypes showed association with both FSAP plasma measurements, but not with IS.Increased plasma FSAP antigen levels and activity were associated with IS and all main etiologic subtypes, suggesting a possible role for FSAP in the pathophysiology of IS, irrespective of the underlying etiology.

    View details for DOI 10.1111/j.1538-7836.2012.04692.x

    View details for PubMedID 22409238

  • TGF-beta signaling, tumor microenvironment and tumor progression: the butterfly effect. Frontiers in bioscience (Landmark edition) Joshi, A., Cao, D. 2010; 15: 180-94

    Abstract

    Transforming growth factor-beta (TGF-beta) signals through receptor serine/threonine kinases and intracellular Smad effectors, regulating numerous epithelial cell processes. TGF-beta plays a crucial role in the cancer initiation and progression through tumor cell autonomous signaling and interactions with tumor microenvironment, but is featured with a butterfly effect upon the stages of tumorigenesis. TGF-beta signaling acts as a suppressor of epithelial cell tumorigenesis at early stages, but promotes tumor progression by enhancing migration, invasion, and survival of the tumor cells during the later stages. TGF-beta signaling also cross-talks with other cell survival signaling pathways. Tumor microenvironment contains many distinct cell types, which substantially influences the tumor cell growth and survival, and the invasion and metastasis. TGF-beta in the microenvironment, produced by cancer and/or stromal cells, is high and negatively correlates with disease progression and patient prognosis. Therefore, TGF-beta may affect tumor progression by multiple mechanisms in addition to its direct action on tumor cells, and the diversities of TGF-beta signaling in tumors imply a need for caution to TGF-beta-targeted strategies of tumor prevention and/or therapeutics.

    View details for PubMedID 20036814

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