Summary Statement/Abstract Multiple sclerosis (MS) is the most common demyelinating disease, affecting approximately 400,000 people in the United States and 2.5 million people worldwide. It is not clear what causes MS, but many believe that it is because our own immune system attacks oligodendrocytes that generate myelin. However, the current therapies that dampen our immune system can only relieve the symptoms but not cure the disease itself. Therefore, it is urgent to find novel therapeutic approaches that can cure the disease, for instance by promoting remyelination. The central nervous system has great potential to regenerate oligodendrocytes and remyelinate in response to myelin damage, however the ability of remyelination is greatly diminished in the MS lesions. Two major reasons are known to prevent efficient remyelination in MS lesions: 1) damaged myelin cannot be efficiently cleared, thereby preventing formation of new oligodendrocytes, and 2) newly generated and/or existing oligodendrocytes have lost the ability to form new myelin. We have identified a key regulator – Quaking (protein name: Qki; gene name: Qk) – that is potent to overcome both obstacles. Firstly, we discovered that Qki is a key regulator of phagocytosis of microglia. Depletion of Qki in microglia greatly reduced the phagocytic activity of microglia, which is critical for clearance of myelin debris and consequently remyelination. Secondly, we discovered that Qki is a major regulator of oligodendrocyte differentiation and myelin homeostasis by regulating lipid metabolism of both newly formed oligodendrocytes and existing oligodendrocytes in the demyelinating lesions. Mature myelin has been considered an inert material for decades. However, our study showed that mature myelin is in fact a very dynamic material through exploiting our genetic systems by depleting Qki in mature myelinating oligodendrocytes of adult mice. The comparative lipidomic and transcriptomic analyses identified Qki as an essential factor for myelin lipid biosynthesis by controlling the transcription of the lipid metabolism genes, particularly those for fatty acid desaturation and elongation, via coactivation of the peroxisome proliferator- activated receptor beta (PPARβ)-retinoid X receptor alpha (RXRα) complex. These findings were corroborated by functional rescue experiments with brain penetrant PPARβ/RXRα agonists, KD3010 and bexarotene. We hypothesize that restoring lipid metabolism by activating PPARβ/RXRα/Qki function will help remyelination in MS through two ways: 1) activating microglia’s function to clear myelin debris, consequently promoting oligodendrocyte regeneration, and 2) enhancing lipid generation of existing and newly generated oligodendrocytes. To test this hypothesis, we propose the following three specific aims. To test this hypothesis, we propose the following three specific aims: 1) To investigate the role of Qki/PPARβ in microglial phagocytosis in clearing myelin debris and prom...