It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non-- coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in the C9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--directional transcription and production of repeat associated non--ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer's disease, Huntington's disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters willtherefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.

Looks at major neurodegenerative diseases affected by RNA toxicity Explores multiple disease mechanisms triggered by RNA metabolism Taken together, the chapters provide insight on potential therapeutic strategies

Autorentext
Rita Sattler is an Associate Professor of Neurobiology at the Barrow Neurological Institute in Phoenix, AZ. She received her master and doctorate degree in Neurophysiology from the University of Toronto in Toronto, Canada where she studied mechanisms of neurodegeneration in stroke. As a postdoctoral fellow at Johns Hopkins University, Dr. Sattler focused her research on studies of synaptic biology and glutamate receptor function. Her current research combines her expertise in neurodegeneration and synaptic function, and is aimed at the elucidation of synaptic dysfunction in neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The Sattler laboratory primarily uses human patient-derived induced pluripotent stem cells differentiated into neurons and glial cells as a disease models and employs state of the art molecular, biochemical, physiological and imaging technologies to identify novel disease pathways and therapeutic targets. Christopher Donnelly is an assistant professor of neurobiology and a member of the Live Like Lou Center for ALS Research at the University of Pittsburgh School of Medicine in Pittsburgh, PA. He received his Ph.D. in Molecular Biology and Genetics at the University of Delaware where he studied RNA trafficking and local translation during axon regeneration. As a postdoctoral fellow at Johns Hopkins University School of Medicine, Dr. Donnelly employed patient derived induced pluripotent stem cell (iPSCs) neurons to study the pathogenic mechanisms underlying mutations that cause Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). These studies revealed RNA-based mechanisms of neurotoxicity and defects in the nucleocytoplasmic transport pathway as drivers of disease. Dr. Donnelly's lab at the University of Pittsburgh currently focuses on employing human iPSC-derived cultures and Drosophila models to elucidate the pathogenic mechanism that contributeto neurodegeneration. Specifically, his lab studies how genetic mutations alter nucleocytoplasmic transport of RNA and proteins and developed a photokinetic approach to understand the triggers and consequences of intracellular protein aggregation that are pathological hallmarks of neurodegenerative diseases.

Inhalt
RNA Metabolism in Neurodegenerative Diseases.- Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes.- RNA Editing Deficiency in Neurodegeneration.- RNA Nucleocytoplasmic Transport Defects in Neurodegenerative Diseases.- RNA Degradation in Neurodegenerative Disease.- RNP Assembly Defects in Spinal Muscular Atrophy.- Stress Granules and ALS: A Case of Causation or Correlation?.- Deregulation of RNA Metabolism in Microsatellite Expansion Diseases.- Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD.- Senataxin, a Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration.- Lost in Translation Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases.