Extended Research done at Neuroscience Program Elio Academy of Biomedical Sciences

Neurodegeneration

Extended Neuroscience Research Project by Riyaa Sri Ramanathan

Introduction

Etymologically, the word "neurodegeneration" is composed of the prefix "neuro-," which designates nerve cells or neurons, and "degeneration," which refers to the process of losing structure or function of tissues or cells. Thus, neurodegeneration corresponds to any pathological condition primarily affecting neurons and leading to neurodegenerative diseases. Diseases arising through neurodegeneration represent a large group of neurological disorders with clinical and pathological characteristics affecting specific subsets of neurons in specific functional systems in the body, resulting in deterioration of brain function. This deterioration gradually causes a loss of cognitive abilities such as memory and decision-making.

Among the hundreds of different disorders, so far attention has been mainly focused only on a handful, with the most notable being Parkinson's disease(PD), Huntington's disease(HT), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease(AD). A large proportion of the less publicized diseases have essentially been ignored.

The most consistent risk factor for developing a neurodegenerative disorder, especially AD or PD, is increasing age. It can be anticipated that over the next generations, the proportion of elderly citizens with the proportion of people affected by neurodegenerative disorders will be doubled. Compounding the problem is that several approved drugs alleviate symptoms of several neurodegenerative diseases, their chronic use is often associated with debilitating side effects, and none seems to stop the progression of the degenerative process.

Categorization of neurodegenerative disorders is based on the predominant clinical feature of the disease and the topography of the predominant lesion. For example, neurodegenerative disorders of the CNS are first grouped into diseases of the cerebral cortex, basal ganglia, the brain stem and cerebellum, or the spinal cord. Then, a disease may be further classified within each group based on its main clinical features. For instance, the group of diseases that predominantly affect the cerebral cortex may be divided into dementia-related and non dementia-related conditions.

Causes of Neurodegeneration

The causes of Neurodegenerative diseases are unknown and are being speculative till date. Reasons surrounding the etiology of neurodegenerative disorders that are becoming widely accepted include:

Genetic mutations.
A buildup of toxic proteins in the brain.
A loss of mitochondrial function.
The creation of neurotoxic molecules.

Although the cause may vary, experts generally agree that the result of these causes is the promotion of apoptosis or programmed cell death, which can result in various neurodegenerative diseases as well.

Current classifications of neurodegenerative diseases are based on a clinicopathological approach defined by presenting symptoms and signs linked to neuropathological findings. Approach to the classification should be reassessed if the usefulness of the clinicopathological approach for diagnosis and treatment in current neurological practice is not considered. It is more appropriate to classify neurodegenerative diseases by their molecular characteristics and redefine the diseases as the consequence of biochemical processes. This helps reveal the pathogenic mechanisms common to some of these diseases and paves the way to new therapeutic avenues that may be effective in several unrelated neurodegenerative diseases.

Different Signaling Pathways impacted in Neurodegeneration

Aging Brain

Aging is a primary risk factor for decreased mental agility and vigor and for age-related cognitive decline in individuals with apparently normal aging brains. Neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, and stroke are most commonly found among those over the age of 55. With neural aging, functional ability and competence that are necessary for mental wellbeing are not developed.

Neural aging is how neural cells in the brain and peripheral nervous system deteriorate structurally and functionally over time. It is associated with a decline in the brain's sensory, motor and cognitive functions.

Factors that contribute to neural aging includes Oxidative damage, Mitochondrial dysfunction, impaired molecular waste disposal, impaired DNA repair, aberrant neuronal network activity, stem cell exhaustion, glial cell activation and inflammation, impaired adaptive stress response signaling, dysregulated neuronal calcium homeostasis, altered nutrient sensing, telomere attrition, genomic instability, cellular senescence, epigenetic alterations and altered intercellular communication.

Research in aging and neuroscience has revealed multiple hallmarks of brain aging at the molecular, cellular, and systems levels. As they involve highly interdependent and interactive signaling pathways and regulatory systems, none of the hallmarks of brain aging occur in isolation.

Classification of Neurodegenerative diseases

The most popular categorization of neurodegenerative disorders is still based on the predominant clinical feature or the topography of the predominant lesion, or often on a combination of both. Neurodegenerative disorders of the CNS are grouped into diseases of the cerebral cortex, the basal ganglia, the brainstem and cerebellum, or the spinal cord. Then, a given disease may be further classified within each group based on its main clinical features. The group of diseases that predominantly affect the cerebral cortex may be divided into dementing (e.g., AD) and non dementing conditions.

Diseases predominantly involve the basal ganglia, a series of deep nuclei located at the base of the forebrain, including the caudate nucleus putamen, globus pallidus, substantia nigra, subthalamic nucleus, red nucleus, and some thalamic and brainstem nuclei, are essentially characterized by abnormal movements. In addition, based on the phenomenology of the abnormal movements, diseases of the basal ganglia can be classified as hypokinetic or hyperkinetic. Hypokinetic basal ganglia disorders are epitomized by PD (Parkinson's Disease), in which the amplitude and velocity of voluntary movements are diminished or nonexistent. Aside from PD, parkinsonism is found in various other diseases of the basal ganglia. In some diseases such as striatonigral degeneration, there is only parkinsonism, but in others, often called parkinson-plus syndromes occurs where there is parkinsonism plus signs of cerebellar ataxia(e.g., olivopontocerebellar atrophy), orthostatic hypotension(e.g., Shy-Drager syndrome), or paralysis of vertical eye movements(e.g., progressive supranuclear palsy). Hyperkinetic basal ganglia disorders, on the other hand, are epitomized by HD (Huntington's Diseases) and essential tremors. Although hyperkinetic basal ganglia disorders are as diverse as hypokinetic ones, their accurate classification makes them less problematic because specific disease markers such as gene mutations exist for several of these syndromes.

Classification of neurodegenerative diseases of the cerebellum and its connections can be grouped into three main neuropathological types:

Cerebellar cortical atrophy (lesion confined to the Purkinje cells and the inferior olives).
Pontocerebellar atrophy (lesion affecting several cerebellar and brain structures).
Friedreich ataxia (lesion affecting the posterior column of the spinal cord, peripheral nerves, and the heart).

However, several other diseases of the cerebellum and its connections cannot be situated in one of these categories such as dentatorubral degeneration, in which the most conspicuous lesions are in the dentate and red nuclei, and Machado-Joseph disease, in which degeneration involves the lower and upper motor neurons, the substantia nigra, and the dentate system.

The neurodegenerative diseases that predominantly affect the spinal cord are ALS and spinal muscular atrophy, in which the most severe lesions are found in the anterior part of the spinal cord. In addition, another group of neurodegenerative that are considered, but not always, because of their chronic course and unknown etiopathogenesis not showing structural abnormalities include torsion dystonia, Tourette syndrome, essential tremor, and schizophrenia. Various brain-imaging studies and electrophysiological investigations have revealed functional abnormalities in all of these singular neurodegenerative disorders but have not revealed their chemical neuroanatomical substrates.

Some fall under classification not because of neuro pathological hallmarks but because of their common molecular defect. These includes HD, spinal cerebellar atrophy and myotonic dystrophy falling into the category of the trinucleotide-repeat diseases; Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and fetal familial insomnia into the category of the prion diseases; PD, progressive supranuclear palsy, and diffuse Lewy body dementia fall into the category of the synucleinopathies and corticobasal degeneration, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and Pick disease fall into the category of the tauopathies.

Onset and Progression of Neurodegenerative disease

Onset of symptoms does not correlate with the onset of the disease as there is significant cellular redundancy in neuronal pathways. Symptoms correspond to a neurodegenerative stage, when the number of residual neurons in a pathway falls below the number required to maintain normal functioning of the affected pathway. Thus depending on the rapidity of the evolving nature of the neurodegenerative process, the onset of the disease occurs at some earlier time, ranging from a few months to several years.

The rate of neuronal death remains about the same throughout the natural course of the disease. Neurodegeneration of cells can be populated using standard clinical, radiological, and biochemical measurements depending on the criticality and the stage of occurrence of the disease. It is well interpreted that clinical progression may reflect a small number of neurons dying rapidly at any given point in time.

Another impact of neurodegeneration is the shortening of the life expectancy of affected patients. This mainly occurs when neurological conditions impair the ability to control or execute vital functions such as respiration, heart rate, or blood pressure. One such disease is ALS in which the loss of lower motor neurons innervating respiratory muscles leads the patient to succumb to respiratory failure. In some disorders, like Friedreich ataxia, the neuronal loss can cause serious cardiac problems such as heart failure. Though certain neurodegenerative diseases directly cause death, most instead facilitate the occurrence of secondary health problems that carry a high mortality rate.

Conclusion

Neurodegenerative diseases are associated with either intracellular or extracellular proteinaceous aggregates that play a pathogenic role in the death of many subsets of neurons in various brain diseases. One such classic example is Alzheimer's. Featured with NFTs and senile plaques, it could be the appropriate example to be classified as a "proteinopathic" neurodegenerative disease. Role of amyloid beta protein (Aβ) in the initiation of Alzheimer's and the outlined molecular scenario by which Aβ can activate the cascade of events ultimately responsible for dementia and cell death in AD, thereby witnessing the state of neurodegeneration in humans.

Sources

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Sally Robertson, B.Sc. "What Is Neurodegeneration?" News, News Medical, 4 Feb. 2021, https://www.news-medical.net/amp/health/What-is-Neurodegeneration.aspx.
Przedborski, Serge, et al. "Neurodegeneration: What Is It and Where Are We?" The Journal of Clinical Investigation, American Society for Clinical Investigation, Jan. 2003, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC151843/.
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Statement of Purpose

Since my second grade, my interest in participating in academic competitions through North South Foundation, a non-profit organization has helped me enhance my Math and Science knowledge. Fun time doing home experiments & school clubs engrossed my interest in STEM fields. Until 5th grade, my only wish was to qualify for nationals, stand on the podium, and receive one of the top 10 coveted trophies. I feel the most profound pleasure when I see my tall shelves stacked up with golds and silvers. But, alas, I failed to score high, and averaged below par in the last science bee competition held in MIT. However, during my visit to MIT, I found the first stepping stone for my passion as I had an opportunity to attend a guided session to compete in the Brain Bee competition conducted by neuroscientists and brain bee winners.. Discussions were about the brain, neurons and nervous systems. My brain got fascinated, the connections were intact, my rewarding pathway got ignited and I decided to learn about the mystery organ - THE BRAIN.

In my 6th grade, the year when COVID - 19 pandemic hit hard on the entire world in 2020, all the competitions were conducted remote. Year of isolation at home allowed me to open my curiosity towards the subject of Neuroscience. I decided to give a try to attend NSF brain bee. I spent my summer learning more about the subject. The subject mesmerized me in different ways, whether it is the new questions or the hidden truths, most of all, the content started to pour out in me. This time, I was determined to be one of the contestants competing for the championship prize. I had said to myself, “No matter what, I would be announced as the first place winner, and my name would come in the ‘bee book’ for future competitors to read.” More than the competition, I felt I should be a part of it. As I had started to prepare, I faced difficulties in understanding the key concepts and memorizing the facts in The Brain Facts book. Continued hassles and my determination to imbibe the knowledge of it, paved the way to take part in Brain bee coaching lessons conducted by the organization. Those workshops helped me to develop a deeper passion for neuroscience, enabling me to understand the concepts in the Brain Facts book published by Society for Neuroscience., and study certain chapters of the Neuroscience: Science of the brain book published by British Neuroscience Association. My workshop mentor, Aditi Kona, wrote a personal mail to my mom highlighting my interest in the subject and reasoning levels in asking questions or interpreting the topics. She strongly recommended my parents that I may have a future in this field while others were just taking steps to see signs of interest. I was a regional winner scoring 23/25, and 33/35 in nationals, and ended up taking the National Championship in finals. That moment I decided that I should pursue my career in Neuroscience. The same year, I attended another competition by Dr. Anwesha Banerjee, Neuroscientist from I Start Valley and won a cash prize.

To progress further, during the 7th-grade summer, I decided to attend molecular medicine workshops. Through my school teacher's recommendation, I got an opportunity to participate in the summer workshops conducted by Rosetta Institute of Biomedical Research. Workshops I attended were Cellular and Molecular Biology & Medicinal Chemistry to familiarize with drug discovery and design. Through the Cellular and Molecular Biology course, I got an opportunity to interact with Dr. Juhi Ojha, Doctor of Philosophy, Molecular Medicine. Through her, I was chosen to participate in the Extended Neuroscience Research Program by Elio Academy.

My craving for knowledge in this field will get deeper to get involved in research studies. My future aspiration is to become a vascular neurosurgeon and will continue to work towards it.

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