RNA Metabolism in Neurodegenerative Diseases

1. Front Matter

   Pages i-xx

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2. An Epigenetic Spin to ALS and FTD

   • Mark T. W. Ebbert, Rebecca J. Lank, Veronique V. Belzil

   Pages 1-29

3. Mechanism of Splicing Regulation of Spinal Muscular Atrophy Genes

   • Ravindra N. Singh, Natalia N. Singh

   Pages 31-61

4. RNA Editing Deficiency in Neurodegeneration

   • Ileana Lorenzini, Stephen Moore, Rita Sattler

   Pages 63-83

5. RNA Nucleocytoplasmic Transport Defects in Neurodegenerative Diseases

   • Ashley Boehringer, Robert Bowser

   Pages 85-101

6. RNA Degradation in Neurodegenerative Disease

   • Kaitlin Weskamp, Sami J. Barmada

   Pages 103-142

7. RNP Assembly Defects in Spinal Muscular Atrophy

   • Phillip L. Price, Dmytro Morderer, Wilfried Rossoll

   Pages 143-171

8. Stress Granules and ALS: A Case of Causation or Correlation?

   • Nikita Fernandes, Nichole Eshleman, J. Ross Buchan

   Pages 173-212

9. Deregulation of RNA Metabolism in Microsatellite Expansion Diseases

   • Chaitali Misra, Feikai Lin, Auinash Kalsotra

   Pages 213-238

10. Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD

    • Marc Shenouda, Ashley B. Zhang, Anna Weichert, Janice Robertson

    Pages 239-263

11. 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

    • Craig L. Bennett, Albert R. La Spada

    Pages 265-281

12. Lost in Translation: Evidence for Protein Synthesis Deficits in ALS/FTD and Related Neurodegenerative Diseases

    • Erik M. Lehmkuhl, Daniela C. Zarnescu

    Pages 283-301

13. Back Matter

    Pages 303-310

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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 theC9orf72 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. 

• RNA metabolism
• RNA toxicity
• neurodegeneration
• RNA processing
• amyotrophic lateral sclerosis (ALS)

• Department of Neurobiology and Neurology, Dignityhealth St. Joseph’s Hospital, Barrow Neurological Institute, Phoenix, USA

  Rita Sattler

• Department of Neurobiology, University of Pittsburgh, Pittsburgh, USA

  Christopher J. Donnelly

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.

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