Impaired coenzyme A homeostasis in cardiac dysfunction and benefits of boosting coenzyme A production with vitamin B5 and its derivatives in the management of heart failure.

Coenzyme A (CoA) is an essential cofactor required for over a hundred metabolic reactions in the human body. This cofactor is synthesized de novo in our cells from vitamin B5, also known as pantothenic acid, a water-soluble vitamin abundantly present in vegetables and animal-based foods. Neurodegenerative disorders, cancer, and infectious diseases have been linked to defects in de novo CoA biosynthesis or reduced levels of this coenzyme. There is now accumulating evidence that CoA limitation is a critical pathomechanism in cardiac dysfunction too. In the current review, we will summarize our current knowledge on CoA and heart failure, with emphasis on two primary cardiomyopathies, phosphopantothenoylcysteine synthetase and phosphopantothenoylcysteine decarboxylase deficiency disorders biochemically characterized by a decreased level of CoA in patients' samples. Hence, we will discuss the potential benefits of CoA restoration in these diseases and, more generally, in heart failure, by vitamin B5 and its derivatives pantethine and 4'-phosphopantetheine.

Inhibition of NF-κB in astrocytes is sufficient to delay neurodegeneration induced by proteotoxicity in neurons.

BACKGROUND: Most neurodegenerative diseases associated with protein aggregation are hallmarked by activation of astrocytes. However, how astrocytes are activated or which signaling pathways in astrocytes contribute to pathogenesis is not clear. One long-standing question is whether the responses in astrocytes are due to stress or damage in astrocytes themselves, or because of astrocytic responses to cellular stress or damage in neurons. Here, we examine responses in astrocytes induced by expression of disease-associated, aggregation-prone proteins in other cells. We also examine the consequences of these responses in astrocytes in a model for neurodegeneration. METHODS: We first examined a role for intracellular astrocytic responses in a Drosophila model for Spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease), a disease caused by expansion of the polyglutamine (polyQ) stretch in the ATXN3 gene. In this Drosophila SCA3 model, eye-specific expression of a biologically relevant portion of the ATXN3 gene, containing expanded polyQ repeats (SCA3polyQ78) was expressed. In a candidate RNAi screen in the Drosophila SCA3 model, we analyzed whether downregulation of expression of specific genes in astrocytes affected degeneration induced by SCA3polyQ78 expression in Drosophila eyes. We next examined the role of astrocytes in response to proteotoxic stress in neurons induced by SCA3polyQ78 expression or amyloid beta peptides, associated with Alzheimer's disease. RESULTS: Eye-specific expression of SCA3polyQ78 resulted in the presence of astrocytes in the eye, suggesting putative involvement of astrocytes in SCA3. In a candidate RNAi screen, we identified genes in astrocytes that can enhance or suppress SCA3polyQ78-induced eye degeneration. Relish, a conserved NF-κB transcription factor, was identified as an enhancer of degeneration. Activity of Relish was upregulated in our SCA3 model. Relish can exert its effect via Relish-specific AMPs, since downregulation of these AMPs attenuated degeneration. We next examined Relish signaling in astrocytes on neurodegeneration. Selective inhibition of Relish expression specifically in astrocytes extended lifespan of flies that expressed SCA3polyQ78 exclusively in neurons. Inhibition of Relish signaling in astrocytes also extended lifespan in a Drosophila model for Alzheimer's disease. CONCLUSIONS: Our data demonstrate that astrocytes respond to proteotoxic stress in neurons, and that these astrocytic responses are important contributors to neurodegeneration. Furthermore, our data demonstrate that activation of NF-κB transcription factor Relish in astrocytes, induced by proteotoxic stress in neurons, enhances neurodegeneration, and that specific Relish inhibition in astrocytes extends lifespan. Our data provide direct evidence for cell-non-autonomous contributions of astrocytes to neurodegeneration, with possible implications for therapeutic interventions in multiple neurodegenerative diseases.