Neurological Disorders

Neurological disorders and diseases include a diverse group of conditions that affect the central and peripheral nervous systems. These include Alzheimer's disease (AD) and other dementias, multiple sclerosis (MS), Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease and epilepsy, among others. The symptoms of these diseases vary widely but often involve impairments to memory, sensation, emotion, movement and other cognitive and physical functions.

Neurological disorders can be caused by various molecular changes that ultimately disrupt normal brain and neuron function. These changes can arise from genetic mutations or environmental influences, or a combination of the two.

Molecular changes as a basis for disease

Aggregation of misfolded proteins

One common observation in neurodegenerative diseases is the buildup of misfolded proteins that damage and kill neurons. In Alzheimer's disease, amyloid-beta peptides are produced through the abnormal cleavage of the amyloid precursor protein (APP). These peptides aggregate to form plaques outside neurons. In addition, tau protein, which normally helps maintain the structure of neurons, can become hyperphosphorylated and aggregate into neurofibrillary tangles inside the neurons. (1)

In Parkinson's disease, the protein alpha-synuclein misfolds and aggregates to form Lewy bodies, which are primarily found within neurons. The accumulation of these bodies contributes to the death of dopaminergic neurons in the substantia nigra, a region of the brain important for movement. (2)

In ALS, the aggregation of various proteins, such as SOD1 (superoxide dismutase 1), TDP-43 (TAR DNA-binding protein of 43 kilodalton) and FUS (fused in sarcoma), are implicated in the disease's pathology. These aggregates can cause motor neuron death, leading to muscle weakness and eventually paralysis. (1)

Changes in signaling

Changes in signaling in response to injury or disease can also lead to neuronal dysfunction and clinical symptoms. For example, neuropathic pain is a type of chronic pain that typically arises from injuries or diseases of the nervous system, including multiple sclerosis. The dorsal horn of the spinal cord is where sensory information from the peripheral nervous system is transmitted to the central nervous system. After a nerve injury, the neurons in the dorsal horn can become hyper-responsive or sensitized and can result in an amplification of pain signals. (3)

Multiple sclerosis (MS) is a chronic disease of the nervous system in which the body's immune system attacks the protective sheath (myelin) that surrounds nerve fibers, causing communication problems between the brain and the rest of the body. Although its exact cause is not understood, it’s clear that dysregulated immune signaling are involved in the development and progression of MS. The molecular trigger for this immune response is still unknown, but genetic factors, such as variations in the HLA-DRB1 gene, and environmental factors, like vitamin D deficiency and viral infections, are thought to contribute to disease development. (4)

In Parkinson's disease, the inability to move normally stems from the degeneration of dopaminergic neurons found in the midbrain. This neuronal death results in a decrease in the neurotransmitter dopamine, which is needed for smooth, purposeful movement. The resulting dopamine deficiency inhibits neurons in the thalamus and brainstem, thereby suppressing the motor functions they regulate. (1)

Dysfunction of Cellular Organelles

In neurodegenerative diseases, nerve damage and death often result from dysfunction in cellular organelles such as mitochondria, lysosomes or the endoplasmic reticulum. For example, in Parkinson's disease, mutations in the genes PINK1 and PARKIN, which are involved in mitochondrial quality control, result in mitochondrial dysfunction. Mitochondria are the cells’ powerhouses and they produce energy in the form of adenosine triphosphate (ATP). Compromised mitochondrial function results in decreased ATP production and an increase in reactive oxygen species (ROS), which can damage other cellular components. Moreover, damaged mitochondria can release proteins that trigger programmed cell death, or apoptosis, contributing to neuronal loss. (5)

Impaired mitochondria are also involved in the development and progression of AD. Mitochondrial trafficking, which is essential for supplying ATP at nerve terminals, is significantly disrupted in neurons affected by AD. This shortage of ATP can harm communication between neurons, leading to memory problems and cognitive decline. It also contributes to synaptic degeneration, synaptic loss and ultimately, neuronal death. (5)

Genetic factors

Genetic mutations that alter normal protein function or expression can affect neuron function. For instance, in Huntington's disease, a mutation in the HTT gene results in the production of an abnormally long version of the huntingtin protein (mHTT) with an excessively long sequence of glutamine amino acids. This abnormal huntingtin protein disrupts normal signaling pathways through several mechanisms. (6)

First, it can directly interact with other signaling pathway components and prevent them from carrying out their normal functions. One example is the interaction between mHTT and the transcription factor CREB-binding protein (CBP), inhibiting CBP’s transcriptional activity. mHTT can also interfere with mitochondrial function, causing energy deficiencies and oxidative stress that can further disrupt cellular signaling. Lastly, mHTT contributes to the abnormal regulation of intracellular calcium levels, which affects multiple calcium-dependent signaling pathways and causes dysregulated neuronal activity and ultimately cell death. (6)

Environmental factors

Various environmental factors are thought to influence the onset and progression of neurodegenerative diseases. These include exposure to heavy metals and chemicals, use of tobacco and alcohol, poor nutrition, physical inactivity and stress, which can cause oxidative stress, inflammation and DNA damage. However, while these may increase the risk of developing a neurological disease, they are usually not the sole cause and often interact with genetic and other lifestyle factors. (7)

Recent research has suggested that nutritional habits that disrupt the gut microbiota may be involved in Alzheimer's and Parkinson's diseases, and fecal microbiota transplantation therapy has shown promising results. (8) Further, environmental chemicals that alter systems such as the dopamine system, a key neurotransmitter system implicated in Parkinson's disease, are being studied for their potential role in disease progression. (9)

The relatively new field of exposomics considers the totality of an individual's environmental exposures and the resulting biological outcomes and consequences. This may further our understanding of neurological diseases by helping to elucidate the complex interaction of environmental factors with genetics and biological processes involved in these conditions. (10)

References

1. Luo, L. Principles of Neurobiology (First Edition), Garland Science, Taylor & Francis Group, LLC, 2016.

2. Sweeney P, et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener. 2017 Mar 13;6:6. doi: 10.1186/s40035-017-0077-5.

3. Tsuda M, Koga K, Chen T, Zhuo M. Neuronal and microglial mechanisms for neuropathic pain in the spinal dorsal horn and anterior cingulate cortex. J Neurochem. 2017 May;141(4):486-498. doi: 10.1111/jnc.14001.

4. Ghasemi N, Razavi S, Nikzad E. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. doi: 10.22074/cellj.2016.4867.

5. Reddy PH. Role of mitochondria in neurodegenerative diseases: mitochondria as a therapeutic target in Alzheimer's disease. CNS Spectr. 2009 Aug;14(8 Suppl 7):8-13; discussion 16-8. doi: 10.1017/s1092852900024901.

6. Li S, Li XJ. Multiple pathways contribute to the pathogenesis of Huntington disease. Mol Neurodegener. 2006 Dec 16;1:19. doi: 10.1186/1750-1326-1-19.

7. Ayeni EA, et al. Neurodegenerative Diseases: Implications of Environmental and Climatic Influences on Neurotransmitters and Neuronal Hormones Activities. Int J Environ Res Public Health. 2022 Sep 30;19(19):12495. doi: 10.3390/ijerph191912495.

8. Wang H, Yang F, Zhang S, Xin R, Sun Y. Genetic and environmental factors in Alzheimer's and Parkinson's diseases and promising therapeutic intervention via fecal microbiota transplantation. NPJ Parkinsons Dis. 2021 Aug 11;7(1):70. doi: 10.1038/s41531-021-00213-7.

9. Rappold PM, et al. Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci USA. 2011 Dec 20;108(51):20766-71. doi: 10.1073/pnas.1115141108.

10. Tamiz AP, Koroshetz WJ, Dhruv NT, Jett DA. A focus on the neural exposome. Neuron. 2022 Apr 20;110(8):1286-1289. doi: 10.1016/j.neuron.2022.03.019.