Research in my laboratory is directed at understanding the role of iron, copper, and zinc in the pathogenesis of neurodegenerative conditions of protein misfolding such as sporadic Creutzfeldt-Jakob disease (sCJD), Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Ongoing investigations are focused on the function of prion protein in systemic and brain iron metabolism, the cross-talk between prion protein and Alzheimer precursor protein and A-beta, and the underlying cause of iron imbalance in sCJD and AD brains. Considerable effort is being directed at developing a disease-specific pre-mortem diagnostic test for sCJD and AD based on the change in brain iron status with disease progression. The ultimate goal is to identify common pathogenic processes leading to metal dyshomeostasis in sCJD, AD, PD, and HD, and to develop therapeutic strategies based on restoring metal homeostasis in diseased brains.
A variety of experimental systems are used for these studies, including primary and transformed cells of neuronal, hematopoietic, hepatic, and intestinal origin transfected to express relevant proteins, C. elegans models expressing normal and mutant prion protein, and mouse models representing these disorders. Adequate training and safe facilities for performing the studies are accessible.
Tripathi AK, Haldar S, Qian J, Beserra A, Suda S, Singh A, Hopfer U, Chen SG, Garrick MD, Turner JR, Knutson MD, Singh N. (2015) Prion protein promotes uptake of NTBI by hepatocytes through Zip14 and DMT1. Free Radic Biol Med. 2015 Apr 7. pii: S0891-5849(15)00162-8. doi: 10.1016/j.freeradbiomed.2015.03.037. PMID: 25862412
Haldar S, Tripathi AK, Qian J, Bessera A, Suda S, McElwee M, Turner J, Hopfer U, Singh N. (2015) Prion protein promotes kidney iron uptake via its ferrireductase activity. J Biol Chem Feb 27;290(9):5512-22. doi:10.1074/jbc.M114.607507. Epub 2015 Jan 8. PMID: 25572394.
Singh N. The role of Iron in prion disease and other neurodegenerative diseases. (2014) Invited review, Plos Pathog. 10(9):e 1004335. PMID: 25232824.
Singh N, Haldar S, Tripathi AK, Horback K, Wong J, Sharma D, Beserra A, Suda S, Anbalagan C, Dev S, Mukhopadhyay CK, Singh A. (2014) Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. Antioxidants & redox signaling, 20(8):1324-1363. PMID: 23815406 PMCID: PMC3935772.
Singh N, Haldar S, Tripathi AK, McElwee MK, Horback K, Beserra A. (2014) Iron in Neurodegenerative Disorders of Protein Misfolding: A Case of Prion Disorders and Parkinson's Disease. Antioxidants & redox signaling, Epub 2014/02/12. doi: 10.1089/ars.2014.5874. PMID: 24512387.
Singh A, Haldar S, Horback K, Tom C, Zhou L, Meyerson H, and Singh N. (2013) Prion protein regulates iron transport by functioning as a ferrireductase. Journal of Alzheimers Dis 35: 541-552. Selected for press release by the journal. PMID:23478311.
Haldar S, Beveridge A, Wong J, Singh A, Galimberti D, Borroni B, Zhu X, Blevins J, Greenlee J, Perry G, Mukhopadhyay C, Schmotzer C., Singh N. (2013) A low molecular-weight ferroxidase is increased in the CSF of sCJD cases: CSF ferroxidase and transferrin as diagnostic biomarkers for sCJD. Antioxid Redox Signal. 2013 April 16. PMID:23379482.
Singh A, Qing L, Kong Q, Singh, N. (2012) Change in the characteristics of ferritin induces iron imbalance in prion disease affected brains. Neurobiol Dis 45: 930-938. PMID:22182691.
Singh A, Beveridge AJ, Singh, N. (2011) Decreased CSF transferrin in sCJD: a potential pre-mortem diagnostic test for prion disorders. PloS ONE, 6(3): e16804. doi:10.1371/journal.pone.0016804. Selected for press release by the journal. PMID: 21408069 PMCID: PMC3052312.
Singh N, Singh A, Das D, Mohan ML. (2010) Redox control of prion and disease pathogenesis. Antioxidants & redox signaling, 12:1271-94. PMID: 19803746 PMCID: PMC2864664.
Singh A, Mohan ML, Isaac AO, Luo X, Singh N. (2009) Prion protein modulates cellular iron metabolism: Implications for prion disease pathogenesis. PLoS ONE 4: e4468. PMCID: PMC2637434.
Singh A, Isaac AO, Lu, X, Mohan ML, Bartz J, Kong K, Cohen M, Singh, N. (2009) Abnormal brain iron homeostasis in human and animal prion disorders. PLoS Pathogens 5:e1000336. PMCID: PMC2652663. Selected as 'Featured Research' in February 2009 issue of Plos Pathogens. Featured in 'Nature Journal club' 460: 669, 2009.
Singh A, Kong Q, Luo X, Petersen RB, Meyerson H, Singh N. (2009) Prion protein (PrP) knock-out mice show altered iron metabolism: A functional role for PrP in iron metabolism. Plos ONE 4:e6115. PMID: 19568430. PMCID:PMC2699477. Published in the autumn 2009 issue of Prion Science. Prionics AG 15.