Frontiers in Clinical Drug Research - CNS and Neurological Disorders: Volume 7

Atta-ur-Rahman, Zareen Amtul

• Publisher: Bentham Science Publishers
• Year: 2020
• ISBN:
  9789811447525
• Topic: Physical Sciences
• Subtopic: Clinical Chemistry

Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of central nervous system (CNS) and other nerve disorders. The scope of the book series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of contemporary molecular targets involved in neurological and CNS disorders. Reviews presented in the series are mainly focused on clinical and therapeutic aspects of novel drugs intended for these targets. Frontiers in Clinical Drug Research - CNS and Neurological Disorders is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critical information for developing clinical trials and devising research plans in the field of neurology. The seventh volume of this series features reviews that cover the following topics related to the treatment of neurodegenerative diseases, epilepsy and stroke: -Fatty Acid Amides as a New Potential Therapeutic Agent in Multiple Sclerosis -Epileptic Seizures Detection Based on Non-Linear Characteristics Coupled with Machine Learning Techniques -Hampering Essential Tremor Neurodegeneration in Essential Tremor: Present and Future Directions -The Potential Therapeutic Role of the Melatoninergic System in Treatment of Epilepsy and Comorbid Depression -Modeling Neurodegenerative Diseases Using Transgenic Model of Drosophila -Genetic Basis in Stroke Treatment: Targets of Potent Inhibitors

Modeling Neurodegenerative Diseases Using Transgenic Model of Drosophila

Brijesh Singh Chauhan¹, Amarish Kumar Yadav¹, Roshan Fatima², Sangeeta Arya¹, Jyotsna Singh¹, Rohit Kumar¹, Saripella Srikrishna^{1, *}

¹ Cell and Neurobiology Laboratory, Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005, India

² National Center for Biological Sciences, Bangalore-560097, India

Abstract

From the past several decades, neuroscientists have been focusing on understanding the mechanisms of various human neurodegenerative diseases using different models such as Mouse, Rat, Zebrafish, worm and the Drosophila. Among them, the Drosophila, with a short generation time and genetic amenity, has emerged as a vital and prevailing model system to explore multiple aspects of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic lateral sclerosis, etc. In this chapter, we have presented various molecular, genetic and therapeutic approaches employed to model human neurodegenerative diseases using Drosophila. Furthermore, we also present the worldwide prevalence of neurodegenerative diseases, along with a survey of published literatures of research conducted in the last two decades on major neurodegenerative diseases employing transgenic Drosophila, to evaluate where we stand.

Keywords: Neurodegeneration, Senile plaques, Neurofibrillary tangles, α-Synuclein, Huntingtin, CAG repeat, MARCM system, GAL4 /UAS binary system, CRISPR-Cas system, Therapeutics.

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^* Corresponding author Saripella Srikrishna:Cell and Neurobiology Laboratory; Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi.-221005, India; E-mail; [email protected]

INTRODUCTION

Neurodegenerative disease refers to the gradual loss of neurons of central nervous system (CNS) and peripheral nervous system (PNS) leading to structural and functional damages. The CNS includes brain and spinal cord which control most functions of the body and mind, while PNS includes cranial nerves, peripheral nerves, nerve roots, and neuromuscular junctions positioned outside the brain and spinal cord [1]. Most common neurodegenerative diseases are Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Frontotem-

poral dementia (FTD), Spinocerebellar ataxia (SCA), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS) [2]. The symptoms of neurodegeneration also manifest in certain other conditions like neuroinfections (due to bacteria and viruses), head trauma, stroke, brain tumors etc. [1]. Here, we are focusing on four most prevalent neurodegenerative diseases i.e., AD, PD, HD, and ALS which are quite straight forward for modeling in fruit flies.

In Alzheimer’s disease (AD), primarily two candidates, Amyloid-β and Hyper-phosphorylated Tau proteins have been implicated. Over expression/ mutation of the concerned genes lead to neuronal cell death and progressive loss of memory. The amyloidogenic mode of enzymatic action on Amyloid precursor protein (APP) results in Amyloid aggregates over a period of time to form Amyloid plaques. Although, normal function of Amyloid-β is not well understood, plaques evoke numerous neurotoxic effects. On the other hand, hyper-phosphorylated Tau protein leads to formation of neurofibrillary tangles (NFTs). Tau protein is also implicated in the progression of Parkinson’s disease, suggesting the susceptibility of AD patients to develop PD symptoms [3]. Several lines of research also indicates greater chances of developing AD like symptom in PD patients and vice versa [4, 5]. This might be due to the presence of the common culprit, reactive oxygen species (ROS)/ reactive nitrogen species (RNS), which act as linking agents for neurodegenerative diseases including AD, PD, and HD [6].

Parkinson’s disease (PD) is the most common movement disorder. The major proteins involved in PD progression include SNCA (OMIM 163890), Parkin/PARK2 (OMIM 602544), DJ-1 (OMIM 602533) and LRRK2 (OMIM 609007). Mutation and/or misregulation of the genes concerned with these proteins cause neuronal cell death, importantly dopaminergic neurons loss, which ultimately hampers the secretion of dopamine [17].

Huntington’s disease (HD), which falls under Polyglutamine (PolyQ) disease group, is a hereditary disease, characterized by progressive loss of brain cells, mainly in ganglion region, and exhibits destruction of mental ability. Previous studies reported that alteration in dopamine (DA) neurotransmission was found in HD patients and also in genetic mouse models of the disease [7, 8]. The modulation in DA transmission level affects the behavioral flexibility and leads to increased risk of Huntington disease [7, 8]. The key protein involved in HD is Huntingtin protein encoded by HTT (OMIM 613004) gene. Mutations in this gene lead to growing CAG repeats translated into a PolyQ stretch. The increasing PolyQ stretches manifest in the form of enhancement of motor neuron degeneration. A report revealed that a fifty eight year old male suffering with HD was diagnosed with a coexistence of motor neuron complication, which is an indication of Amyotrophic lateral sclerosis [9].

In ALS, the motor neurons lacking neuronal muscle nourishment cause atrophy or progressive loss of motor neurons affecting the daily work schedule [10]. There are mainly two form of ALS, sporadic and familial. Sporadic ALS is more common and is caused without a clear reason known, accounts upto 90-95% of the cases, while familial ALS shows genetic inheritance and accounts for approximately 5-10% of the cases. However, mutations in genes such as CHCHD10, TBK1, NEK1, C9orf72 and SOD1, enhances the possibility of ALS [11, 12]; In America, familial ALS cases are more prominent due to mutation in genes c9orf72 (chromosome 9 open reading frame 72) and SOD1 (superoxide dismutase) [13]. Several reports revealed that mutation in SOD1 gene causes...