Multiple sclerosis (MS) is a debilitating neurological disease resulting from a destruction of myelin and myelin-forming cells (oligodendrocytes). Myelin membranes are produced by the oligodendrocytes in the central nervous system (CNS) to allow for high speed and high fidelity impulse conduction along axons through saltatory conduction. Oligodendrocytes synthesize up to three times their weight in myelin membrane per day and each oligodendrocyte fully myelinates axonal segments in a 24-hour period. Myelination requires a very high metabolic rate and thus entails consumption of large amounts of ATP and oxygen implicating mitochondrial function as a vital component in synthesizing and maintaining myelination of the CNS. High energy requirements for myelination by oligodendrocytes may be particularly relevant to either the success or failure of remyelination in MS. Additionally, a second main physiological function of mitochondria is to produce reactive oxygen species (ROS) that must also is stringently regulated in the mature oligodendrocyte. High ROS output by oligodendrocyte mitochondria is particularly relevant to mechanisms of demyelination. The protein tyrosine phosphatase SHP-1 is a potentially important molecule in MS since it is a major negative regulator of the immune system and regulates cell signaling in oligodendrocytes. Our lab discovered that SHP-1 is expressed in oligodendrocytes and plays an important role for proper myelination of the CNS. Importantly, we recently showed that SHP-1 controls the constitutive production of ROS by oligodendrocytes. We hypothesize that SHP-1 regulates both ATP and ROS production by mitochondria in oligodendrocytes. We further hypothesize that SHP-1 controls these mitochondrial functions primarily through modulation of STAT1 and STAT3 activation in oligodendrocytes. The goal of this project is to determine how SHP-1 mediates alterations in mitochondrial function through the regulation of STAT1 and STAT3 activation. Our goal is to first determine how SHP-1 regulates STAT1 and STAT3 activation in oligodendrocytes. We will then determine the effects of STAT1 and STAT3 activation on oligodendrocyte mitochondrial function by assessing various parameters including mitochondrial basal respiration, ATP production, proton leak, maximal respiratory capacity, membrane potential, ROS production, and electron chain complex expression. Finally, we will determine if SHP-1 dependent regulation of STAT1 or STAT3 activation alters the susceptibility of the oligodendrocytes to mitochondrial-mediated apoptosis. These studies will provide us with insight into mechanism of mitochondrial dysfunction that can cause significant oligodendrocyte dysfunction in neurodegenerative diseases including MS.
Mitochondrial dysfunction is becoming increasingly relevant as a major driver of neurodegenerative diseases including multiple sclerosis (MS). We have discovered that the Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1) (a major negative regulator of immune signaling) regulates mitochondrial function in the myelin-forming glia of the CNS, oligodendrocytes. As SHP-1 activity is known to be affected by inflammatory signaling, we propose that mitochondria in oligodendrocytes may become dysfunctional and cause cell damage in MS.