S1C). and in thePpt1-KO mice, phosphorylated-S6K-1 (p-S6K1) levels, which Monastrol inversely correlate with lifespan, are markedly elevated. Most importantly, resveratrol (RSV), an antioxidant polyphenol, elevated the NAD+/NADH ratio, levels of ATP, p-AMPK, PGC-1 and SIRT1 while decreasing the level of p-S6K1 in both INCL fibroblasts and inPpt1-KO mice, which showed a modest increase in lifespan. Our results show that disruption of adaptive energy metabolism and increased levels of p-S6K1 are contributing factors in INCL pathogenesis and provide the proof of principle that small molecules such as RSV, which alleviate these abnormalities, may have therapeutic potential. == INTRODUCTION == Neurodegenerative disorders are some of the most intractable human ailments for which the development of effective treatment remains challenging. Neurodegeneration is a devastating manifestation in the majority of more than 40 lysosomal storage disorders that affect 1 in 7000 live-born infants (1,2). Although these storage disorders are rare, they provide a window of opportunity to uncover the pathogenic mechanisms of more common neurodegenerative diseases. Moreover, understanding the molecular mechanism(s) of pathogenesis of these rare disorders may advance our knowledge of the pathogenic mechanism(s) in more common neurodegenerative disorders and facilitate the development of rational therapeutic strategies. Neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, represent the most common (1 in 12 500 births) hereditary neurodegenerative storage disorders that primarily affect children (38). Mutations in at least eight different genes underlie various types of NCLs. As a group, NCLs share a number of clinical and pathological features including psychomotor retardation, retinal blindness, myoclonus, seizures, intracellular autofluorescent storage material and reduced lifespan (38). The infantile NCL (INCL), also known as infantile Batten disease, is a rare (1 in >100 000 births) but one of the most lethal neurodegenerative storage disorders of childhood caused by inactivating mutations in the palmitoyl protein thioesterase-1 (Ppt1) gene (9). Children afflicted with INCL are normal at birth but by 1118 months of age they develop psychomotor retardation and complete retinal degeneration causing blindness. By age 4, they have no detectable brain activity. These children remain in a vegetative state for another 68 years before death (38). Despite the Monastrol fact that the genetic basis of INCL was discovered more than a decade ago (9), the precise molecular mechanism(s) of INCL pathogenesis remains poorly understood and, currently, there is no effective treatment for this disease. We have previously reported that neurodegeneration in INCL is at least partially caused by excessive endoplasmic reticulum (ER) and oxidative stresses, which mediate neuronal apoptosis (10,11) and neuroinflammation (12,13). We also reported thatPpt1-knockout (Ppt1-KO) mice (14), which recapitulate virtually all clinical and pathological features of human INCL including dramatically reduced lifespan (15), manifest high levels of oxidative stress, which adversely affects mitochondrial function activating caspase-9 pathway of neuronal apoptosis (11,16). Mitochondria communicate and interact with each other as well as with various cellular organelles such as the ER in order to meet the ever changing cellular energy needs and to protect the cells from excessive Ca2+release as well as mutations in mitochondrial DNA, events that typify aging and neurodegenerative processes (17). Despite varying clinical manifestations of neurodegenerative disorders, the fact that neurons rely heavily on oxidative energy metabolism suggests a unified mechanism that involves dysfunction in mitochondrial energy homeostasis (18). New insight into the role(s) of mitochondria in neuronal function and viability has been facilitated by the discovery of the peroxisome proliferator-activated receptor- (PPAR) coactivator-1 (PGC-1), which also regulates thermogenesis (19). Interestingly, we uncovered that thermogenesis in children afflicted with INCL is abnormally regulated (20). In addition to its role in mitochondrial biology, PGC-1 also regulates several key metabolic programs that go beyond mitochondrial biogenesis and oxidative phosphorylation. For example, PGC-1-null mice manifest defects in adaptive energy Monastrol metabolism Monastrol and show clinical manifestations such as stimulus-induced myoclonus, dystonic posturing and frequent limb clasping, characteristic of certain neurodegenerative Rabbit Polyclonal to STK39 (phospho-Ser311) disorders (21), including INCL. Impaired mitochondrial energy metabolism due to the disruption of mitochondrial function might negatively affect the ATP/AMP ratio. The cells, especially neurons, in turn respond by adjusting both the.
S1C)