"Neurodegeneration is one of society's critical issues over the next 50 years"
- Chan Zuckerberg Science Initiative - Dec. 2018
Neurological disorders and Neurodegeneration
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Neurodegeneration is characterized as a progressive loss of structure and function of neurons and can lead to variety of motor and cognitive impairments. Although the underlying mechanisms involved in neurodegeneration can differ, neuronal death and degeneration is common across a variety of neurological conditions, including Chemotherapy-induced Peripheral Neuropathy (CINP), Parkinson’s Disease (PD), Mild Cognitive Impairment (MCI) and amyotrophic lateral sclerosis (ALS).
Chemotherapy-induced Peripheral Neuropathy (CIPN)
Chemotherapy-Induced Peripheral Neuropathy is a common neurological disorder that adversely affects nerve fibers and/or neuronal bodies of primary sensory neurons. This loss of neuron structure and function can lead to dose reduction or discontinuation of chemotherapy treatment as well as a decrease in the quality of life of patients. Greater than 70% of individuals treated with platinum-based chemotherapeutic agents experience symptoms of peripheral neuropathy, including pain and loss of motor function as well as learning and memory impairments. Following chemotherapy, levels of tumor protein p53 increase, microtubules, which serve as a highway for the transport of proteins necessary for neuronal health, break down. HDAC6 inhibitors have been shown to decrease the accumulation of p53, rebuild ‘microtubule highways’ to restore neuronal protein transport leading to a reversal or attenuation of neuropathic pain symptoms.
Eldridge et al., (2020) Toxicology Pathology, 48(1), 190-201; Banach et al., (2017) Brain and Behaviour, 7(1);
Bennett et al., (2014) Nature Reviews Neurology. 10, 326-336; Maj et al., (2017) Front. Mol. Neurosci. 10(108);
Ma et al., (2018) Cancer. 124(11):2289-2298
Certain human brain cells selectively die off in Parkinson’s disease. Among cells that produce the chemical messenger dopamine (green), an active AGTR1 gene (labeled in magenta) sets these vulnerable cells apart.
Parkinson's Disease (PD)
Parkinson's disease is a neurological disorder that causes unintended or uncontrollable movements, such as shaking, stiffness, and difficulty with balance and coordination. It is often age-related and is a progressive disorder that is caused by degeneration of nerve cells in the part of the brain called the substantia nigra, which controls movement by modulation of dopamine in the brain. Accumulating evidence suggests that the serotonergic system is involved in the pathophysiological basis of PD, with 5-HT receptor activation showing efficacy in alleviating multiple motor and non-motor PD symptoms including tremors, L-DOPA-induced dyskinesia, cognitive impairment, mood disorders and degeneration of dopamine neurons.
Ohno Yet al., (2015). Progress in Neurobiology. 2015;134:104-21.
Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD)
MCI is believed to serve as the prodromal stage of clinical Alzheimer’s Disease, acting as a transitional stage between normal brain aging and dementia, and is characterized by memory impairment and absence of diagnosed dementia. AD is a progressive neurodegenerative disease that is the most common form of dementia and is associated with mild memory loss that worsens over time, leading to severe cognitive decline. Currently, AD is the sixth leading cause of death in the United States, and upon diagnosis, survival rates typically range anywhere between four and twenty years. Scientific identifiers in AD include amyloid beta plaques and hyperphosphorylated Tau protein.
Bland J. (2016) Integr Med (Encinitas);15(2):12-4.
M. A. Busche and B. T. Hyman (2020) Nature Neuroscience 23, 1183–1193.
M. A. Busche and B. T. Hyman, "Synergy between amyloid-β and tau in Alzheimer’s disease" Nature Neuroscience 23, 1183–1193, 2020
Amyotrophic Lateral Sclerosis (ALS)
ALS is a progressive neurodegenerative disease that results in loss of motor function through progressive degeneration of motor neurons in the brain and spinal cord. In ALS, TDP-43 protein mislocates from the cell nucleus to the cytoplasm, axonal transport of key proteins (i.e., mitochondria) is impaired, and neurites, which help to connect neurons together become damaged. HDAC6 inhibitors have shown therapeutic efficacy in restoring neuronal function in ALS, by decreasing TDP-43 displacement, restoring axonal protein transport and improving neurite growth.
Neumann et al (2006). Science. 314(5796);
Fazal et al (2021) EMBO. 40:e106177
