Publication Date

2012-04-26

Availability

Embargoed

Embargo Period

2013-10-18

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Biochemistry and Molecular Biology (Medicine)

Date of Defense

2012-03-29

First Committee Member

Sanjoy K. Bhattacharya

Second Committee Member

Ralf Landgraf

Third Committee Member

Antonio Barrientos

Fourth Committee Member

Vineet Gupta

Fifth Committee Member

Paul Thompson

Abstract

Deimination refers to conversion of protein-bound arginine into citrulline. In contrast to global hyper-deimination in the brain and eyes, we have found local hypo-deimination in the retinal ganglion cell layer of patients and in a transgenic mouse model of multiple sclerosis. REF, an RNA and export binding protein, was specifically found to undergo loss of deimination in multiple sclerosis, resulting in functional changes in RNA binding. mRNAs for SNARE complex and mitochondrial ATPase complex are enriched by deiminated REF. We confirmed the presence of REF in dendritic site and mitochondrial surface. Only the deiminated form of REF interacts with the eIF4F complex in both cytosolic and mitochondrial surface. Down-regulation of deimination or REF results in decreased neurite outgrowth and reduced the mitochondrial ATP synthase activity compared to the control. Restoration of deimination in the optic nerve results in dramatic improvement in visual function and elongation of neurite length in isolated neurons. Together, these findings support a key role for protein deimination in dendritic protein synthesis and mitochondrial mRNA transport and identify a potential new pathway for early events in the pathogenesis of multiple sclerosis and possibly other neurodegenerative diseases.

Keywords

Deimination; Dendritic protein synthesis; Multiple sclerosis; Mitochondria; ATP synthase

Download

Share

COinS