Principal Investigator: Tomohiro Nakamura, PhD
Research Focus: Neurodegenerative disorders (Alzheimer’s, Parkinson’s, and Huntington’s diseases)
Our group is focused on a nitric oxide (NO)-mediated posttranslational modification called S-nitrosylation, whereby an NO group reacts with a critical cysteine thiol of a specific protein to regulate its function, akin to the effect of phosphorylation. Excessive generation of NO in the nervous system may constitute a fundamental pathological process in neurodegenerative disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Our research is directed towards understanding the molecular mechanisms of how protein S-nitrosylation contributes to mitochondrial dysfunction, protein misfolding, and increased cell death under neurodegenerative conditions.
Nakamura Lab: In-depth
The global prevalence of neurodegenerative disorders, such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), is increasing with extended life expectancy. Although precise cellular and molecular mechanisms underlying neurodegeneration still remain enigmatic, key features of these devastating disorders have been identified, including elevated oxidative/nitrosative stress, mitochondrial dysfunction, protein misfolding/aggregation, synapse loss, and decreased neuronal survival. In particular, aberrant S-nitrosylation reactions can occur with aging or environmental toxins that generate excessive NO, affecting protein misfolding, mitochondrial fragmentation, synaptic function, apoptosis or autophagy. Our research discovered how aberrantly S-nitrosylated proteins play a crucial role in the pathogenesis of neurodegenerative diseases, including AD and PD. Our findings provided insight into the pathophysiological role of aberrant S-nitrosylation pathways that enhance our understanding of molecular mechanisms leading to neurodegenerative diseases and point to potential therapeutic interventions.
A growing literature suggests that over 1000 proteins are S-nitrosylated in cell systems. However, the mechanism by which specific protein S-nitrosylation occurs in cell signaling pathways is less well investigated. Interestingly, the recent discovery by our groups of protein-protein transnitrosylation reactions (transfer of an NO group from one protein to another) has revealed a unique mechanism whereby NO can S-nitrosylate a particular set of protein thiols, and represents a major class of nitrosylating/denitrosylating enzymes in mammalian systems. Thus, these studies opened a new research field in the area and implicated that elucidation of additional transnitrosylation cascades will further our understanding of NO-mediated signaling pathways leading to neurodegenerative conditions.
1) Sunico CR, Sultan A, Nakamura T, Dolatabadi N, Parker J, Shan B, Han X, Yates JR 3rd, Masliah E, Ambasudhan R, Nakanishi N, Lipton SA. Role of sulfiredoxin as a peroxiredoxin-2 denitrosylase in human iPSC-derived dopaminergic neurons. Proc Natl Acad Sci USA. 2016; 113(47):E7564-E7571.
2) Eichmann C, Tzitzilonis C, Nakamura T, Kwiatkowski W, Maslennikov I, Choe S, Lipton SA, Riek R. S-Nitrosylation Induces Structural and Dynamical Changes in a Rhodanese Family Protein. J Mol Biol. 2016; 428(19):3737-51.
3) Akhtar MW, Sanz-Blasco S, Dolatabadi N, Parker J, Chon K, Lee MS, Soussou W, McKercher SR, Ambasudhan R, Nakamura T, Lipton SA. Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat Commun. 2016; 7:10242.
4) Nakamura T, Lipton SA. Protein S-nitrosylation as a therapeutic target for neurodegenerative diseases. Trends Pharmacol Sci. 2016;37(1):73-84.
5) Choi MS, Nakamura T, Cho SJ, Han X, Holland EA, Qu J, Petsko GA, Yates JR 3rd, Liddington RC, Lipton SA. Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in Parkinson's disease models. J Neurosci. 2014;34(45):15123-31.
6) Okamoto S, Nakamura T, Cieplak P, Chan SF, Kalashnikova E, Liao L, Saleem S, Han X, Clemente A, Nutter A, Sances S, Brechtel C, Haus D, Haun F, Sanz-Blasco S, Huang X, Li H, Zaremba JD, Cui J, Gu Z, Nikzad R, Harrop A, McKercher SR, Godzik A, Yates JR 3rd, Lipton SA. S-Nitrosylation-mediated redox transcriptional switch modulates neurogenesis and neuronal cell death. Cell Rep. 2014;8(1):217-28.
7) Nakamura T, Tu S, Akhtar MW, Sunico CR, Okamoto S, Lipton SA. Aberrant protein S-nitrosylation in neurodegenerative diseases. Neuron. 2013;78(4):596-614.
8) Nakamura T, Lipton SA. Emerging role of protein-protein transnitrosylation in cell signaling pathways. Antioxid Redox Signal. 2013;18(3):239-49.
9) Qu J, Nakamura T, Cao G, Holland EA, McKercher SR, Lipton SA. S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by β-amyloid peptide. Proc Natl Acad Sci USA. 2011;108(34):14330-5.
10) Nakamura T, Wang L, Wong CC, Scott FL, Eckelman BP, Han X, Tzitzilonis C, Meng F, Gu Z, Holland EA, Clemente AT, Okamoto S, Salvesen GS, Riek R, Yates JR 3rd, Lipton SA. Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. Mol Cell. 2010;39(2):184-95.
11) Cho DH, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-Nitrosylation of Drp1 mediates b-amyloid-related mitochondrial fission and neuronal injury. Science. 2009;324(5923):102-5.
12) Fang J, Nakamura T, Cho DH, Gu Z, Lipton SA. S-Nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson's disease. Proc Natl Acad Sci USA. 2007;104(47):18742-7.
13) Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA. S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature. 2006;441(7092):513-7.
14) Yao D, Gu Z, Nakamura T, Shi ZQ, Ma Y, Gaston B, Palmer LA, Rockenstein EM, Zhang Z, Masliah E, Uehara T, Lipton SA. Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity. Proc Natl Acad Sci USA. 2004;101(29):10810-4.
Complete Publication List on PubMed