Meet the editor

Dr. Hegde is Associate Professor at Houston Methodist Research Institute (HMRI), Houston, Texas, USA. He also holds adjunct faculty appointments at Weill Medical College of Cornell University and Texas A&M University. Dr. Hegde directs a research program focused on delineating the molecular insights into the involvement of genome damage/repair responses in human brain pathologies and developing novel mechanism-based treatment

strategies for these diseases. Amyotrophic Lateral Sclerosis is a major focus of Dr. Hegde's research program, with recent publications in prestigious journals that include *Nature Communications*, *PNAS* and *JBC* on this topic. Dr. Hegde's research has been continuously funded by multiple grants from the National Institutes of Health and other foundations. He serves on the editorial boards of half a dozen journals.

Contents

**Section 1**

Lateral Sclerosis

Dysfunction in ALS

Which to Combat the Disease

*by Fatima Pedrosa Domellöf*

**Section 2**

*by Joy Mitra and Muralidhar L. Hegde*

*by Haibo Wang and Muralidhar L. Hegde*

Mechanisms of Genome Stability in Motor Neurons *by Arijit Dutta, Robert Hromas and Patrick Sung*

*by Luis Bermúdez-Guzmán and Alejandro Leal*

**Preface XI**

New Paradigm of Genome Instability and DNA Repair Defects in ALS **1**

**Chapter 1 3**

**Chapter 2 27**

**Chapter 3 41**

**Chapter 4 59**

Emerging Etiopathology and Implications **79**

**Chapter 5 81**

**Chapter 6 99**

Senataxin: A Putative RNA: DNA Helicase Mutated in ALS4—Emerging

Pathological Interaction between DNA Repair and Mitochondrial

The Role of Extracellular Vesicles in the Progression of ALS and Their Potential as Biomarkers and Therapeutic Agents with

The Extraocular Muscles Are Selectively Spared in ALS

*by Changho Chun, Alec S.T. Smith, Mark Bothwell and David L. Mack*

The Role of TDP-43 in Genome Repair and beyond in Amyotrophic

Molecular Basis of DNA Repair Defects in FUS-Associated ALS: Implications of a New Paradigm and Its Potential as Therapeutic Target

### Contents



Preface

Despite significant advances in our understanding of the pathological and biochemical changes that are associated with the motor neuron disease

and progression that will ultimately allow scientists and clinicians to design effective ways to develop improved treatment protocols for ALS patients.

The book contains eight chapters that cover both basic research/methodologies and therapeutic advances in the area of ALS, with a particular focus on emerging science and concepts. Both common and rare subsets of ALS are covered, including sporadic and inherited disease. Chapters address various topics, such as ALS-associated etiological factors TDP-43, FUS, and senataxin alongside emerging research on genome repair defects, mitochondrial dysfunction, exosomes, non-coding RNA/ biomarker discovery, R-loop as well as the recent advances in ALS therapy and utilization of axonal transport for drug delivery. These chapters are contributed by esteemed scientists from the United States, Italy, Sweden, Belgium and Costa Rica.

The editor would like to express his sincere gratitude to the chapter authors for their

**Dr. Muralidhar L. Hegde, PhD, FABAP**

Houston Methodist Research Institute, Affiliate of Weill Medical College, New York, Houston, Texas, USA

Department of Neurosurgery, Center for Neuroregeneration,

invaluable contributions.

Amyotrophic Lateral Sclerosis (ALS), no cure currently exists. Although available treatments can temporarily slow disease progression, they are unable to prevent neuronal death. The groundbreaking discoveries in 2006 that implicated toxicity of the RNA/DNA-binding proteins TDP-43 and FUS in ALS triggered a flurry of research activities towards understanding the neurobiology and pathology of these proteins. Resultantly, the involvement of more than a dozen additional factors (e.g., C9ORF72, profilin, senataxin, etc.) was subsequently reported. Still, how these factors trigger neuronal dysfunction remains unclear, which has been a roadblock in the development of more effective therapeutics. The relative contribution of 'gain-of-toxicity' or 'loss-of-function' of ALS-linked factors is a key question. While initial research focused on RNA processing defects, recent studies demonstrated a widespread imbalance in genome damage versus repair rates, thus opening avenues for potential DNA repair-based therapeutics. This book debates recent advances in our understanding of the ALS group of diseases and outlines future directions for research activities towards finding a cure for these debilitating brain diseases. The diverse but complementary chapters highlight the need for an overarching approach to unravel the fundamental mechanisms of disease initiation
