S-nitrosylation of UCHL1 induces its structural instability and promotes [alpha]-synuclein aggregation

Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson's disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggr...

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Published inScientific reports Vol. 7; p. 44558
Main Authors Kumar, Roshan, Jangir, Deepak K, Verma, Garima, Shekhar, Shashi, Hanpude, Pranita, Kumar, Sanjay, Kumari, Raniki, Singh, Nirpendra, Sarovar Bhavesh, Neel, Ranjan Jana, Nihar, Kanti Maiti, Tushar
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group 01.03.2017
Subjects
Alzheimer's disease
Apoptosis
Biotechnology
Enzymes
Hydrolase
Laboratories
Lewy bodies
Movement disorders
Mutation
Neurodegenerative diseases
Neurons
Nitric oxide
Nucleation
Parkinson's disease
Pathogenesis
Polymorphism
Protein gene product 9.5
Proteins
Rotenone
Synuclein
Ubiquitin
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Summary:Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson's disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggregate is still unclear. We report here that UCHL1 undergoes S-nitrosylation in vitro and rotenone induced PD mouse model. The preferential nitrosylation in the Cys 90, Cys 152 and Cys 220 has been observed which alters the catalytic activity and structural stability. We show here that nitrosylation induces structural instability and produces amorphous aggregate, which provides a nucleation to the native α-synuclein for faster aggregation. Our findings provide a new link between UCHL1-nitrosylation and PD pathology.
ISSN:2045-2322
DOI:10.1038/srep44558