**Meet the editors**

Dr L. Miguel Martins is currently a tenured Programme Leader with the MRC Toxicology Unit. His research interests have focused on understanding the fundamental mechanisms regulating cell death and survival. He conducted his Ph.D. studies under the supervision of Professor William Earnshaw at The Johns Hopkins School of Medicine (USA) and The University of Edinburgh (Scotland).

This work involved the characterization of caspase activation in apoptosis. Subsequently, his research focus shifted from the execution of apoptotic cell death to the modulation of this process by upstream signaling networks. He worked as a post-doctoral researcher in the laboratory of Dr Julian Downward at The Imperial Cancer Research Fund/Cancer Research UK in London, England. During this period, Dr L. Miguel Martins was involved in the identification of key mitochondrial proteins that regulate apoptotic cell death. Among several mitochondrial controllers of cell death, his work led to the characterization of a mitochondrial serine protease, Omi/HtrA2. Currently, the work in his laboratory focuses on dissecting signal transduction pathways that regulate mitochondria-dependent apoptosis and understanding how the abnormal activity of such networks might affect cell survival, leading to diseases such as cancer and neurodegenerative diseases.

Dr Samantha H.Y. Loh is currently a Senior Scientist in charge of a Drosophila research facility at the MRC Toxicology Unit. Her main research interests involve using the fruit fly, Drosophila melanogaster, as an animal model system to study molecular and cellular mechanisms involved in human diseases such as cancer and neurodegeneration. She conducted her Ph.D. studies under the

supervision of Professor Michael Ashburner at the Department of Genetics and Churchill College, University of Cambridge (UK). This work involved the molecular and genetic characterisation of the Drosophila Sox (Sry-type HMG box) genes. Subsequently, her research focus shifted onto the emerging field of high throughput RNA interference genetic screens. She worked as a post-doctoral researcher in the laboratory of Professor Pierluigi Nicotera at the MRC Toxicology Unit in Leicester, UK. During this period, she established a high content RNAi screening system and managed a research project to screen for kinases involved in neurite outgrowth and retraction in neuronal culture cells. Her work from this initial in vitro screening system led to the further characterisation of some of the candidate hits in vivo by using the Drosophila model system. Currently, her research focuses on dissecting the molecular and cellular mechanisms of neurodegeneration as well as the signal transduction pathways that regulate mitochondrial-dependent apoptosis.

Contents

**Preface IX** 

Chapter 1 **SIRT2 (Sirtuin2) – An Emerging** 

V. Chandana Epa

Chapter 4 **Chronic Formaldehyde-Mediated** 

Chapter 6 **Melanocortins: Anti-Inflammatory** 

Chapter 7 **Mechanisms and Patterns** 

Chapter 8 **An Overview of Target Specific** 

and Mohammad Tariq

Junye Miao and Rongqiao He

Chapter 5 **Emerging Concepts Linking Mitochondrial** 

**and Neuroprotective Peptides 93**  Carla Caruso, Lila Carniglia, Daniela Durand, Teresa N. Scimonelli and Mercedes Lasaga

**of Axonal Loss in Multiple Sclerosis 121**  Zachary M. Harris and Jacob A. Sloane

Ahmad Al Mutairy, Khalaf Al Moutaery,

Abdulrahman Al Asmari, Mohammed Arshaduddin

**Neuro-Protective and Neuro-Restorative Strategies 153** 

Chapter 2 **Structural and Computational Studies** 

Chapter 3 **Neuroprotective Effects of Neuropeptide** 

Maria Śmialowska and Helena Domin

**Regulator of Neuronal Degeneration 1** 

Tatsuro Koike, Kazuhiko Suzuki and Tomohiro Kawahata

**of Interactions of Metals with Amyloid Beta 15** 

**Impairments and Age-Related Dementia 59** 

**Stress Signalling and Parkinson's Disease 77**  Ana C. Costa, L. Miguel Martins and Samantha H. Y. Loh

**Y and Y2 and Y5 Receptor Agonists** *In Vitro* **and** *In Vivo* **37** 

### Contents

#### **Preface XI**


X Contents



### Preface

Neurodegeneration involves the progressive loss of sypnatic connectivity, neuronal structure and function, and ultimately the demise of neurons. Progressive dysfunction of the nervous system is normally associated with atrophy of the central or peripheral structures and is linked to both hereditary and environmental factors. With an increase in human lifespan worldwide, the prevalence of many neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, Multiple Sclerosis, Amyotrophic Lateral Sclerosis, and others is gradually increasing. However, effective treatments are still lacking. Recent studies have revealed many parallels among this diverse group of disorders, including protein aggregation and mitochondrial dysfunction. Therefore a better understanding of both the molecular and cellular processes that are altered during neurodegeneration will hopefully result in a better understanding of these devastating diseases and possibly new treatments

This book covers some of the recent advances in our understanding of basic biological processes that modulate the onset and progression of neurodegenerative processes. Its purpose it to present a snapshot of ongoing scientific research focused on the understanding of the basis of neurodegeneration in humans.

Through a multidisciplinary approach, here are presented several recent findings from molecular, cellular and model organism studies of neurodegeneration, as well as epidemiology and genetics studies related to clinical aspects of neurodegenerative diseases.

A series of chapters focus on describing how the use of model organisms, such as mouse, *Drosophila* and *Dictyostelium* has helped us in the understanding of the basic biology underpinning neurodegenerative processes. It also contains sections focusing on how endogenous and exogenous toxic agents such as mitochondrial stress, melanocortins and formaldehyde impinge on neuronal function and neurodegeneration.

This book also provides a series of overviews of several neurodegenerative conditions affecting humans such as vascular dementia, neurofibromatosis, stroke, Parkinson's and Alzheimer's diseases*.* 

#### X Preface

In conclusion, a wide variety of conceptually distinct approaches are presented in an attempt to provide an overview on the current understanding of the fundamental basis of neurodegenerative diseases whose incidence has dramatically increased. We wish to thank the authors of each individual chapter for their contribution in summarising their most relevant findings and hope that some of the discoveries outlined here will have a positive impact on the improvement of human health

#### **L. Miguel Martins** and **Samantha H. Y. Loh**

MRC Toxicology Unit University of Leicester United Kingdom

X Preface

In conclusion, a wide variety of conceptually distinct approaches are presented in an attempt to provide an overview on the current understanding of the fundamental basis of neurodegenerative diseases whose incidence has dramatically increased. We wish to thank the authors of each individual chapter for their contribution in summarising their most relevant findings and hope that some of the discoveries

**L. Miguel Martins** and **Samantha H. Y. Loh** 

MRC Toxicology Unit University of Leicester United Kingdom

outlined here will have a positive impact on the improvement of human health

**1** 

 *Japan* 

**SIRT2 (Sirtuin2) – An Emerging** 

**Regulator of Neuronal Degeneration** 

*Hokkaido University Graduate School of Life Science, Sapporo,* 

Tatsuro Koike\*, Kazuhiko Suzuki and Tomohiro Kawahata

SIRT2(sirtuin 2) is one of the mammalian orthologs (sirtuins) of yeast silent information regulator 2 (Sir2) proteins that regulate cell differentiation and calorie restriction (Gan and Mucke, 2008; Nakagawa and Guarente, 2011 for review). In contrast to other family members of sirtuins, SIRT2 is mostly localized in the cytoplasm, and regulates posttranslational modifications of proteins such as microtubules via tubulin deacetylation (North et al., 2003)(Fig. 1). The enzyme catalyzes the hydrolysis of NAD+ and transfer of the acetyl moiety of acetylated alpha-tubulin to the resultant ADP-ribose, thus yielding free alpha-tubulin, 2'-O-acetylated ADP-ribose, and niconinamide. This stoichiometry indicates that its activities are modulated by the status of energy metabolism, and nicotinamide serves as an inhibitor. It has well been appreciated that SIRT2 plays a crucial role in cellular functions including oligodendrocyte differentiation (Li et al., 2007; Ji et al., 2011) and cell cycle (Dryden et al., 2003; Inoue et al., 2007) in non-neuronal cells. So far very few studies have ever addressed the question as to whether its expression in neurons shows any functional significance. We will briefly summarize our results on its functional involvement in axon degeneration, and discuss some of recent findings, highlighting an emerging role of

With long axons and elaborated dendrites, neurons establish the circuitry that receives, stores and transmits information to perform neuronal functions (Horton and Ehlers, 2003). The establishment and maintenance of this circuitry requires a coordinated and widespread regulation of the cytoskeleton and membrane trafficking system. Microtubles, whose building block is a heterodimer of alpha- and beta- tublins, play a pivotal role in this function (Fig. 1). There are multiple pathways through which microtubules are stabilized. For instance, acetylation is mostly observed in stable microtubules in neurons as revealed by their low sensitivity to drug-induced depolymerization (Black and Greene, 1982) or upregulation of acetylated alpha-tubulin in response to trophic factor (Black and Keyser,

SIRT2 in the regulation of neuronal degeneration and plasticity.

**2. Tubulin acetylation and axon stability 2.1 Acetylation and deactylation of tubulin** 

**1. Introduction** 

\*Corresponding Author
