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Global s-nitrosoprotemone identification links UCHL1 to Parkinson disease pathology
Roshan Kumar1, 4, Deepak K Jangir1, Garima Verma2, Shashi Shekhar3, Pranita Hanpude1,4,
Sanjay Kumar1,4, Raniki Kumari1, Neel S Bhavesh2, Nihar R Jana3 and Tushar K Maiti1*
Laboratory of Proteomics and Cellular Signaling, Regional Centre for Biotechnology
(RCB), NCR Biotech Science Cluster, 3rd Milestone Gurgaon-Faridabad Expressway,
Faridabad 121001, India.
Transcription Regulation Group, International Centre for Genetic Engineering and
Biotechnology (ICGEB), Aruna Asaf Ali Marg, New Delhi 110067, India.
Molecular Neuroscience Laboratory, National Brain Research Centre (NBRC),
Manesar, Gurgaon 122051, India.
Manipal University, Manipal, Karnataka 576104, India.
Parkinson disease is characterised by excessive serum nitric oxide level and upregulated
nitric oxide synthase activity. Aberrant level of nitric oxide leads to the covalent binding of NO
moiety to protein cysteine residues and it is one of the main mechanisms of nitric oxide
signalling. Cysteine thiols act as redox switch and regulate various physiological process.
Using a combination of the alkylating biotin switch assay and LC-MS/MS analysis, we have
revealed the S-nitrosoproteome of rotenone induced Parkinson’s disease mouse model brain
and rotenone treated SH-SY5Y cells. A total of 49 and 249 nitrosylated proteins identified in
Parkinson’s mice model brain and rotenone treated SH-SY5Y cells respectively. We have
identified Ubiquitin C-terminal hydrolase 1(UCHL1) as one of the protein which undergoes
nitrosative modification. Cysteine 90,152 and 220 of UCHL1 gets modified under nitrosative
stress condition which regulate its deubiquitinating activity and ubiquitin binding. We have
shown by employing various biophysical approaches that S-nitrosylation of UCHL1 alters its
conformation leading to the formation of amorphous aggregates and constituting one of the
component of Lewy body. Our findings provide a new link between UCHL1-nitrosylation and
Parkinson’s disease pathology.