Oxidative damage to proteins is considered to be one of the major causes of aging and age-related diseases, and thus mechanisms have evolved to prevent or reverse these modifications. Methionine is one of the major targets of reactive oxygen species (ROS), where it is oxidized to methionine sulfoxide (MetO). Recently evidence has accumulated suggesting that methionine oxidation may play an important role in the progression of neurodegenerative diseases like Alzheimer's and Parkinson's disease. Oxidative alteration of Met to Met(O) is reversed by the methionine sulfoxide reductases (MsrA which reduces S-MetO and MsrB which reduces R-MetO). This may prevent irreversible protein damage and as a consequence extend the organism's life span. A major biological role of Msrs is suggested by the fact that the MsrA null mouse (MT) exhibits a neurological disorder in the form of ataxia ("tip toe walking"), is more sensitive to oxidative stress, and has a shorter life span (by~40%) than wild-type (WT) mice. However, a major open question is how these important antioxidants function, and is the methionine oxidation/reduction cycle analogous to the cysteine oxidation/reduction or protein-phosphorylation / dephosphorylation mechanisms involved in cell signaling. The specific aims of Jackob Moskovitz's research is designed to determine how the Msr system affects the function and expression of other proteins as well as to evaluate the role of methionine oxidation in the progression of oxidative stress and age related diseases.
Age-related neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are often associated with proteins functioning improperly. AD patients tend to accumulate β-amyloid plaques, while Lewy bodies containing the protein -synuclein are found in post-mortem PD patients.
Oxidative stress is a key component of many age-related diseases, and the oxidation of protein-bound methionine and cysteine is suggested to play a significant role in protein function and cell physiology. Methionine sulfoxide reductase (Msr) system (consists of MsrA and MsrB) is able to reduce cellular methionine sulfoxide to methionine. Compromised ability of reducing methionine oxidized proteins may lead to accumulation of faulty proteins and shorter life span of the organism.
The aim of our research is to better understand the role of oxidative damage/repair that occurs to proteins, in general, and to brain proteins, in particular (including β-amyloid and α-synuclein). To achieve this goal we utilize molecular biology techniques and proteomic approaches that use both ex-vivo and in vivo systems. Consequently, we hope to determine the possible role of the Msr system in development and progression of neurodegenerative diseases and oxidative-stress related neurological disorders.
Lab Members —
|Yue "Alvin" Deng||Graduate Student||Ph.D. student, University of Iowa|
|Beichen Jiang||Graduate Student||Clinical Research Associate, Merck Inc., China|
|Derek B. Oien||Graduate Student||Boehringer Ingelheim, St. Joseph, MO|