Plasma ATN(I) classification and precision pharmacology in Alzheimer's disease.

Evaluating potential therapies for Alzheimer's disease (AD) depends on use of biomarkers for appropriate subject selection and monitoring disease progression. Biomarkers that predict onset of clinical symptoms are particularly important for AD because they enable intervention before irreversible neurodegeneration occurs. The amyloid-β-tau-neurodegeneration (ATN) classification system is currently used as a biological staging model for AD and is based on three classes of biomarkers evaluating amyloid-β (Aβ), tau pathology and neurodegeneration or neuronal injury.

Investigational treatments for neurodegenerative diseases caused by inheritance of gene mutations: lessons from recent clinical trials.

We reviewed recent major clinical trials with investigational drugs for the treatment of subjects with neurodegenerative diseases caused by inheritance of gene mutations or associated with genetic risk factors. Specifically, we discussed randomized clinical trials in subjects with Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis bearing pathogenic gene mutations, and glucocerebrosidase-associated Parkinson's disease. Learning potential lessons to improve future therapeutic approaches is the aim of this review.

Coordination of cell cycle, DNA repair and muscle gene expression in myoblasts exposed to genotoxic stress.

Upon exposure to genotoxic stress, skeletal muscle progenitors coordinate DNA repair and the activation of the differentiation program through the DNA damage-activated differentiation checkpoint, which holds the transcription of differentiation genes while the DNA is repaired. A conceptual hurdle intrinsic to this process relates to the coordination of DNA repair and muscle-specific gene transcription within specific cell cycle boundaries (cell cycle checkpoints) activated by different types of genotoxins. Here, we show that, in proliferating myoblasts, the inhibition of muscle gene transcription occurs by either a G 1- or G 2-specific differentiation checkpoint.

Histone deacetylase inhibitors in the treatment of muscular dystrophies: epigenetic drugs for genetic diseases.

Histone deacetylases inhibitors (HDACi) include a growing number of drugs that share the ability to inhibit the enzymatic activity of some or all the HDACs. Experimental and preclinical evidence indicates that these epigenetic drugs not only can be effective in the treatment of malignancies, inflammatory diseases and degenerative disorders, but also in the treatment of genetic diseases, such as muscular dystrophies. The ability of HDACi to counter the progression of muscular dystrophies points to HDACs as a crucial link between specific genetic mutations and downstream determinants of disease progression.

TNF/p38α/polycomb signaling to Pax7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration.

How regeneration cues are converted into the epigenetic information that controls gene expression in adult stem cells is currently unknown. We identified an inflammation-activated signaling in muscle stem (satellite) cells, by which the polycomb repressive complex 2 (PRC2) represses Pax7 expression during muscle regeneration. TNF-activated p38α kinase promotes the interaction between YY1 and PRC2, via threonine 372 phosphorylation of EZH2, the enzymatic subunit of the complex, leading to the formation of repressive chromatin on Pax7 promoter.

Epigenetic regulation of skeletal myogenesis.

During embryogenesis a timely and coordinated expression of different subsets of genes drives the formation of skeletal muscles in response to developmental cues. In this review, we will summarize the most recent advances on the "epigenetic network" that promotes the transcription of selective groups of genes in muscle progenitors, through the concerted action of chromatin-associated complexes that modify histone tails and microRNAs (miRNAs). These epigenetic players cooperate to establish focal domains of euchromatin, which facilitates gene transcription, and large portions of heterochromatin, which precludes inappropriate gene expression.

Switch NFix developmental myogenesis.

During development, skeletal muscles adapt to stage-specific functional and metabolic challenges by switching the expression of specific subset of genes. The mechanism that governs these changes is still enigmatic. In a recent issue of Cell, Messina and coworkers shed light on this issue through the identification of a transcription factor--NFix--that coordinates the switch in gene expression at the transition from embryonic to fetal myoblasts.

Chromatin: the interface between extrinsic cues and the epigenetic regulation of muscle regeneration.

Muscle regeneration provides a paradigm by which to study how extrinsic signals coordinate gene expression in somatic stem cells (satellite cells) by directing the genome distribution of chromatin-modifying complexes. Understanding the signal-dependent control of the epigenetic events underlying the transition of muscle stem cells through sequential regeneration stages holds the promise to reveal new targets for selective interventions toward repairing diseased muscles. This review describes the latest findings on how regeneration cues are integrated at the chromatin level to build the transcription network that regulates progression of endogenous muscle progenitors throughout the myogenic program.

Apoptotic death induces Abeta production and fibril formation to a much larger extent than necrotic-like death in CGNs.

In this study we report that apoptotic death of primary cultures of cerebellar granule neurons is accompanied by release of thioflavin-binding proteins - indicative of the presence of beta-sheet structures - and fibril formation in the culture medium. When the same neurons are subjected to an excytotoxic death caused by 100 microM glutamate exposure, the amount of thioflavin binding is markedly reduced. Western blot analysis shows that fibrils contain monomers, dimers and trimers of amyloid-beta (Abeta) which, when observed at the electron microscope, have morphologies reminiscent of fibrils of senile plaques.