Identification of Novel Therapeutic Targets for Polyglutamine Diseases That Target Mitochondrial Fragmentation.

Huntington's disease (HD) is one of at least nine polyglutamine diseases caused by a trinucleotide CAG repeat expansion, all of which lead to age-onset neurodegeneration. Mitochondrial dynamics and function are disrupted in HD and other polyglutamine diseases. While multiple studies have found beneficial effects from decreasing mitochondrial fragmentation in HD models by disrupting the mitochondrial fission protein DRP1, disrupting DRP1 can also have detrimental consequences in wild-type animals and HD models.

Targeting Mitochondrial Network Disorganization is Protective in Models of Huntington's Disease.

Huntington's disease (HD) is an adult-onset neurodegenerative disease caused by a trinucleotide CAG repeat expansion in the gene. While the pathogenesis of HD is incompletely understood, mitochondrial dysfunction is thought to be a key contributor. In this work, we used models to elucidate the role of mitochondrial dynamics in HD.

The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons.

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin () gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD.

Biological Aging and the Cellular Pathogenesis of Huntington's Disease.

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin gene (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life, suggesting that aging may play an active role in pathogenesis. Cellular aging is defined as the slow decline in stress resistance and accumulation of damage over time.

Disruption of mitochondrial dynamics increases stress resistance through activation of multiple stress response pathways.

Mitochondria are dynamic organelles that can change shape and size depending on the needs of the cell through the processes of mitochondrial fission and fusion. In this work, we investigated the role of mitochondrial dynamics in organismal stress response. By using C.

Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways.

Background: The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway activated by disruption of proteostasis in the mitochondria. This pathway has been proposed to influence lifespan, with studies suggesting that mitoUPR activation has complex effects on longevity.

Results: Here, we examined the contribution of the mitoUPR to the survival and lifespan of three long-lived mitochondrial mutants in Caenorhabditis elegans by modulating the levels of ATFS-1, the central transcription factor that mediates the mitoUPR.

Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models.

While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.

Mitochondrial pyruvate carrier regulates autophagy, inflammation, and neurodegeneration in experimental models of Parkinson's disease.

Mitochondrial and autophagic dysfunction as well as neuroinflammation are involved in the pathophysiology of Parkinson's disease (PD). We hypothesized that targeting the mitochondrial pyruvate carrier (MPC), a key controller of cellular metabolism that influences mTOR (mammalian target of rapamycin) activation, might attenuate neurodegeneration of nigral dopaminergic neurons in animal models of PD. To test this, we used MSDC-0160, a compound that specifically targets MPC, to reduce its activity.

Oxidative stress is increased in C. elegans models of Huntington's disease but does not contribute to polyglutamine toxicity phenotypes.

Huntington's disease (HD) is an adult onset neurodegenerative disorder for which there is currently no cure. While HD patients and animal models of the disease exhibit increased oxidative damage, it is currently uncertain to what extent oxidative stress contributes to disease pathogenesis. In this work, we use a genetic approach to define the role of oxidative stress in HD.

Delaying aging is neuroprotective in Parkinson's disease: a genetic analysis in models.

Aging is the greatest risk factor for the development of Parkinson's disease (PD). However, the role of aging in the pathogenesis of PD is not known and it is currently uncertain why the symptoms take many decades to develop when inherited mutations that cause the disease can be present from birth. We hypothesize that there are specific changes that take place during the aging process that make cells susceptible to disease-causing mutations that are well-tolerated at younger ages.

Mitochondrial and cytoplasmic ROS have opposing effects on lifespan.

Reactive oxygen species (ROS) are highly reactive, oxygen-containing molecules that can cause molecular damage within the cell. While the accumulation of ROS-mediated damage is widely believed to be one of the main causes of aging, ROS also act in signaling pathways. Recent work has demonstrated that increasing levels of superoxide, one form of ROS, through treatment with paraquat, results in increased lifespan.