Institute of Neural Regeneration & Tissue Engineering

	Institute of Neural Regeneration & Tissue Engineering

Neurodegeneration

Neurodegenerative Diseases are characterized by progressive dysfunction and death of neural cells and tissue, which results in various forms of movement disorders and cognitive decline over time. Such diseases include Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis (Lou Gehrig’s disease), each of which is described further below.

Parkinson’s Disease is the result of dying dopaminergic neurons in the substantia nigra of the brain, and it is characterized by resting tremor, bradykinesia, and rigidity, and symptoms eventually progress towards dementia. This disease is part of a class of diseases called synucleinopathies, where altered synuclein (pronounced “sin-nuke-lay-in”) proteins conglomerate into intracellular aggregates called Lewy bodies, which are thought to be toxic to the cells and which can be transfered among cells [1]. Although most cases of Parkinson’s disease have not yet been linked to genetic causes, mutations in genes encoding synuclein and LRRK2 have been shown to cause inherited forms of Parkinson’s disease and Lewy body dementia (DLB). New research has linked these mutations to the miro protein on mitochondrial membranes and the inability to remove damaged mitrochondria, thereby creating greater susceptibility to oxidative damage [2]. Recent evidence has also suggested that the symptoms of Parkinson’s are triggered by the interplay of genetic susceptibility and gut bacteria (likely via certain bacterial metabolites that contribute to oxidative damage) [3]. With the loss of dopaminergic signals in Parkinson’s disease, the intricacy and meaning of information encoded in certain neural activity is lost and neural activity becomes more affected by the activity of cholinergic pathways in the basal ganglia. While certain drugs (like dopamine agonists and anticholinergics) and certain procedures like deep brain stimulation can temporarily improve some symptoms of the disease in some patients, they cannot cure it in anyone, and it remains a progressive downhill neurodegenerative disease. Approximately 1 million people in the United States live with the disease, and about 60,000 more cases are diagnosed each year [4-5].

Alzheimer’s Disease is a neurodegenerative disease involving the frontal lobes of the brain where many cognitive processes occur. Therefore the manifestations of the disease may include a variety of symptoms, including memory loss, impaired judgment, confusion, mood swings, and progressive deterioration in many bodily functions and the ability to care for oneself. Like all neurodegenerative diseases, this is currently a progressive and irreversible affliction. It has been generally believed that Alzheimer’s disease is caused by amyloid plaque formations in the brain [6-9], but much evidence suggests that these plaques may be a downstream effect rather than a cause and may not be directly associated with the cognitive dysfunctions of the disease, while phosphorylated tau protein tangles in neurons are more associated with the disease [10-17]. Several areas of the brain may be affected in this disease, including frontoparietal cortex, hippocampus, and other nuclei of the brain, and there is generally decreased cholinergic activity in the forebrain. Drugs for Alzheimer’s tend to increase cholinergic activity by blocking cholinesterase action, and these drugs may slow the progression of dementia in some patients. Some forms of Alzheimer’s disease have been found to be due to inherited mutations in genes like Apo E4, presenilin, amyloid precursor protein, and others. Over 5 million people in the United States have Alzheimer’s disease, and there are nearly half a million new cases diagnosed each year [18-19].

Amyotrophic Lateral Sclerosis (ALS) is the result of death of neurons involved in movement (motor neurons). The death of lower motor neurons in the spinal cord causes weakness and atrophy in muscles, while death of upper motor neurons causes spasticity and dyscoordination. This eventually leads to difficulty moving, speaking, swallowing, and breathing, which can often result in skin ulcers and lung infections similar to spinal cord injury patients. Many cases are related to inherited alterations in the C9orf72 gene (alterations of nucleotide expansions with associated cytoplasmic inclusions, which is a disease mechanism similar to Huntington's Disease or many other pathogenic repeat expansion diseases, although in this case the repeat expansion is a non-coding segment, which likely causes flawed transcriptional, translational, or post-translational processes), or to inherited mutations in the superoxide dismutase gene, which normally functions to remove oxygen free radicals from the body, but when mutated results in higher levels of oxidative damage and inflammation [20]. Riluzole is a drug that may suppress excitatory signaling in neurons, and it is the sole drug approved for ALS in the United States. Although the incidence and prevalence of the disease are not known for certain in the United States, it is estimated that at least 4 people per 100,000 have the disease and approximately 2 people per 100,000 are diagnosed with the disease annually, meaning that about 6,000 people in the United States are diagnosed with the disease each year [21].

Huntington’s Disease is the result of loss of neuronal tissue in the frontal lobe cortex and basal ganglia, particularly the caudate nucleus. The manifestations of the disease include cognitive, behavioral, and movement disturbances. The sudden and dramatic uncontrollable movements of Huntington’s disease are called “chorea,” referring to the “dance-like” movements of swinging arms, and patients may also suffer dystonia, rigidity, memory loss, mood swings, and decline in judgment and cognitive abilities, eventually resulting in dementia. The underlying genetic cause of the disease has been pinpointed as related to the length of abnormal CAG repeats (>40 repeats), which make a polyglutamine string on one end of the huntingtin protein (similar to other trinucleotide repeat disorders like spinocerebellar ataxia), but many details of the pathophysiology of the disease still remain to be understood. Antipsychotic medications are often used to manage the symptoms of the disease, and the prevalence of the disease is estimated to be approximately 5-10 per 100,000 [22-23].

Multiple Sclerosis is sometimes characterized as a neurodegenerative disease, but it may be more fitting to classify it as a neuroimmunological disease since the demyelination appears to be mediated by T-cells and an IgG antibody response in the nervous system and effective treatments include various forms of immunomodulatory agents. However, the cause and effect mechanisms of the disease are not yet fully elucidated. The disease is characterized by demyelination (loss of myelin sheaths around nerve fibers) and the formation of demyelinated plaques in the brain or spinal cord as seen on neuroimaging. Symptoms can include weakness, paralysis, spasticity, ophthalmic nerve problems, bowel and bladder incontinence, and visual disturbances. These symptoms may become worse with stressful or warm environments, and they may remit and relapse over time. It is estimated that over 2 million people in the world have multiple sclerosis, with over 300,000 of those living in the United States [24-25].

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References:

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