Free Neurodegenerative diseases Dissertation Example
Neurodegenerative diseases include a cluster of progressive chronic diseases that are categorized by the steady damage of neurons in separate locations of the Central Nervous System (Gao and Hong 2008, 357). Examples of such conditions include amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia (FTD), spinocerebellar ataxias and Alzheimer’s disease. The neuromuscular junction of a neuron is quite an extraordinary structure that is specifically vulnerable to the neurodegenerative diseases. Nonetheless, it has powerful mechanisms of resisting injury so that it can regenerate (Aaron et al. 2017, 501). The commonly altered cellular pathways of neurodegenerative disorders include transcriptional, protein and mitochondrial homeostasis. For instance, considering Alzheimer’s disease (AD), the disorder is commonly referred to as a synaptopathy, which means there is either damage or loss of the synapses. This damage or loss of the synapses causes an altered neuronal circuitry (Montie 2013, 194).
Today, about five million American citizens are suffering from Alzheimer’s disease; one million United States inhabitants have Parkinson’s disease; four hundred thousand have multiple sclerosis (MS); three hundred thousand have amyotrophic lateral sclerosis (ALS), and approximately thirty thousand have Huntington’s disease. Since neurodegenerative diseases strike mainly from mid- to late-life, the occurrence is expected to ascend as the populace ages. If the situation is left unchecked, thirty years from now, about more than twelve million American citizens may suffer from neurodegenerative diseases.
One of the very common risk factors for neurodegenerative conditions is inflammation (Rebecca 1250). Inflammation involves an intricate cascade of responses that are self-defensive to harmful stimuli. Even though a well-regulated inflammatory process in the body is critical for tissue function and homeostasis, an extreme inflammatory response may be a basis of additional injury to a host cell (Gao and Hong 2008, 359). Since the neural tissues contain possess a restricted cell regenerative and renewal capacity, the central nervous system is highly vulnerable to unregulated autodes tructive immune as well as inflammatory processes. Therefore, inflammation, mainly when it is uncontrolled, it contributes to the loss of neurons in neurodegenerative disorders (Glass et al. 2010, 918).
The mentioned categories of neurodegenerative diseases arise due to various genetic factors. For instance, amyotrophic lateral sclerosis (ALS) may be hereditary through an autosomal recessive, X-linked or autosomal dominant manner. The causative genes for ALS have been acknowledged in approximately five to ten percent of all the ALS cases. Among those, twenty percent of ALS cases arise due to a mutation in the SOD1 gene. About four to five of the ALS cases are as a result of mutations in the FUS and TARDBP genes. More than thirty percent of the ALS cases represent C9ORF72 mutations while the rest of the ALS cases arise because of mutations in senataxin (SETX), VAPB optineurin (OPTN), factor-induced gene 4 and mutations in alsin (Chen et al. 2013, 28).
In the case of FTD (frontotemporal dementia), the genetic cause of FTD is a mutation that takes place in C9orf72. It is vital to mention that recent discoveries have shown without a doubt that ones the C9orf72 gene mutates, familial and sporadic frontotemporal lobar degeneration takes place followed by amyotrophic lateral sclerosis disorder finally in some cases there are presentations of concomitant FTD-ALS (Callister and Pickering-Brown 2014, 84).
For Alzheimer’s disease, the critical gene associated with the development of the disease is the ATP-binding cassette transporter A7 gene (ABCA7). The ABCA7 gene is associated with the elimination of aggregated proteins. Variants are known as LOF (loss-of-function) variants in the ABCA7 gene are leading risk factors for Alzheimer’s disease. Additionally, previous research has indicated the separation of a sporadic TTC3 (tetratricopeptide repeat domain three genes) variant in a family with what is commonly referred to as late-onset Alzheimer disease. Recent research has also indicated that LOF variants are also common in persons affected with Parkinson’s disease, a phenomenon which potentially shows shared pathways in both Parkinson’s disease in addition to Alzheimer’s disease.
184.108.40.206 Amyotrophic lateral sclerosis (ALS)
This condition refers to a neurodegenerative disorder that is progressive and which is associated with the degeneration of the lower and upper motor neuronal system. This disease is frequently fatal, and it is normally asspociated with bulbar signs and spasticity. In spite of the major weakening of the motor system associated with ALS, widespread indication has specified numerous non-motor symptoms like visuoperceptual deficits, cognitive deterioration, as well as language impairments (Gitler et al. 2017, 499). Additionally, the complexity of ASL is such that anatomical and functional cerebral gashes are not only present in the corticospinal tracts and precentral cortices, but in cerebellum, corpus callosum, and visual, temporal and frontal processing cortices (Li et al. 2018, 2).
220.127.116.11 Frontotemporal Dementia (FTD)
FTD refers to a progressive neurological disorder involving attendant underlying pathogens and diverse clinical presentations. The standard presentations of the disease include language difficulties, neuropsychiatric symptoms, and psychiatric syndrome. However, the multiplicity of these presentations increases distinctive diagnostic challenges, which may suggestively influence patient counsel as well as patient care for healthcare providers concerning prognosis and clinical status (Bott et al. 2014, 1)
C9orf72 is a gene which provides instructions for creating a protein that is located in various tissues in a human body. The protein is abundant in neurons (nerve cells) in the brain’s outer layers referred to as the cerebral cortex as well as in specialized neurons of the spinal cord and the brain that control motor neurons. The full common genetic basis for frontotemporal dementia (FTD) in addition to ALS is hexanucleotide repeat expansion that takes place in the primary intron of the C9orf72 genetic factor (Lee et al., 2017, 4766).
1.1.4 Innate Immunity
Innate immunity refers to human body’s natural immune system which is specifically present at birth. The innate immune system is critical for the overall health of a human being, and it comprises the main types of body defenses, which structure the immune system. The innate immunity of a person consists of innate immune cells, skin, as well as chemicals in the blood that gets activated via particular chemical properties of specific antigens. Numerous kinds of white blood cells exist, which constitute the innate immune system and they include monocytes, neutrophils, mast cells, eosinophils, basophils, cytokines, natural killer cells and the complementary system (Gandhi et al. 2010, 3).
Several neurodegenerative diseases critically involve neuroinflammation. Neuro-inflammation involves significant signaling steps associated with activation of the innate immunity, therefore, representing promising therapeutic targets. The motility and complexity of body processes like the microglia processes seem to be compromised with neurodegenerative conditions like ALS and Alzheimer’s disorder in a similar manner that the processes undergo during aging. The microglial cells encompass 10 to 20 % of the glial body cells. These cells are the widespread immune cells located in the CNS. They are involved most often in antigen presentation, production of cytokines and phagocytosis.
The interaction between microglia and neurons in an ordinary human brain act to overpower microglial activation, which promotes neuronal homeostasis. The capacity in which microglial dysfunction causes neurodegeneration through perturbation of signaling over a different microglial-neuronal interaction has been previously demonstrated in people with Nasu-Hakola disease. The Nasu-Hakola disorder is a progressive neurodegenerative disease, which arises due to the lack of function mutations that occur in the cell surface receptor of a microglial TREM2 gene or its intracellular signaling adapter (DAP12).
1.1.5 Toll-like Receptors (TLRs)
Microglia signify the first line defense of the intrinsic immune defense system against most bacterial infections and viral infections that affect the central nervous system. The response of these cells to TLR stimulation takes place via production of cytokines as well as other inflammatory mediators including through augmenting phagocytosis of microorganisms including the aggregated extracellular proteins (Arroyo et al. 2011, 5).
Pro-inflammatory molecules that are raised in neurodegenerative disorders may elevate the expression of TLRs in the cells of the Central Nervous System (Kumar, Kawai & Akira 2009, 622). When these TLRs are activated, in turn, they can also increase the manufacture of local proinflammatory cytokines. Consequently, the function of TLRs in numerous aspects of neurodegenerative disorders has been proposed. An example is Alzheimer’s disease where there is persistent activation of the glial cells without acute inflammation. In patients affected with this disorder, it is specifically critical to determine the exact role of different TLRs in the Aβ recognition as well as in clearance and the glial cell activation. This may give vital clues concerning the mechanisms that are associated with AD-associated neurodegeneration and perhaps create new avenues in searching for novel molecular targets for Alzheimer’s disease therapy and vaccination (Beutler 2009, 1400).
Another example is multiple sclerosis (MS) that involves an adaptive immune response, which is produced after activation and inflammation of the glial cells. In an individual with active multiple sclerosis, central to the lesions and perivascular areas, the TLR expression is elevated and is co-localized with astrocytes and microglia (Arroyo et al. 2011, ).
1.1.6 The use of Drosophila for Ageing Research
It is well recognized that the proinflammatory cytokine levels of the body’s innate immune system elevate in the CNS during the aging process. This phenomenon signifies that, during the aging process, the microglia cells that are located in the brain display a pro-inflammatory profile, which reasonably, underlies their minimized morphological complexity (Andreasson et al. 2016, 8)
Drosophila melanogaster is a fruit fly that has produced significant advances in the underpinnings of several neurodegenerative and neurological disorders by providing information concerning the biological pathways that are impaired in the diseases (McGurk et al. 2015, 378). For instance, combined disease-associated mutations have been discovered through linkage analysis and exome sequencing in proteins like the heterogeneous nuclear ribonucleoproteins in families that have ALS and multisystem proteinopathy, with data from the fly for functional effects. The proteins possess a little complexity prion-like domain such as FUS and TDP-43, and the identified mutations speed up the aggregation process. The fly is, therefore, instrumental in presenting the pathogenicity of the disorder associated with the mutations as well as the association of the prion domain with toxicity. Thus, such an approach provides a deeper molecular appreciation of fundamental biological process that leads to neurodegenerative disorders including how the processes are affected in disease, thereby unveiling the hidden secretes of the functionality of the brain and its responses to aging. (McGurk et al. 2015, 393)
Andreasson, K.I., Bachstetter, A.D., Colonna, M., Ginhoux, F., Holmes, C., Lamb, B., Landreth, G., Lee, D.C., Low, D., Lynch, M.A. and Monsonego, A., 2016. Targeting innate immunity for neurodegenerative disorders of the central nervous system. Journal of Neurochemistry, 138(5), pp.653-693.
Arroyo, D.S., Soria, J.A., Gaviglio, E.A., Rodriguez-Galan, M.C. and Iribarren, P., 2011. Toll-like receptors are key players in neurodegeneration. International Immunopharmacology, 11(10), pp.1-15.
Beutler, B.A., 2009. TLRs and innate immunity. Blood, 113(7), pp.1399-1407.
Bott, N.T., Radke, A., Stephens, M.L. and Kramer, J.H., 2014. Frontotemporal dementia: diagnosis, deficits, and management. Neurodegenerative disease management, 4(6), pp.439-454. Callister, J.B., and Pickering-Brown, S.M., 2014. Pathogenesis/genetics of frontotemporal dementia and how it relates to ALS. Experimental Neurology, 262, pp.84-90.
Chen, S., Sayana, P., Zhang, X. and Le, W., 2013. Genetics of amyotrophic lateral sclerosis: an update. Molecular Neurodegeneration, 8(1), p.28.
Gandhi, R., Laroni, A., and Weiner, H.L., 2010. Role of the innate immune system in the pathogenesis of multiple sclerosis. Journal of Neuroimmunology, 221(1-2), pp.1-18.
Gao, H.M. and Hong, J.S., 2008. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends in Immunology, 29(8), pp.357-365.
Gitler, Aaron D., Paraminder Dhillon, and James Shorter. “Neurodegenerative disease: models, mechanisms, and a new hope.” (2017): 499-502.
Glass, C.K., Saijo, K., Winner, B., Marchetto, M.C. and Gage, F.H., 2010. Mechanisms underlying inflammation in neurodegeneration. Cell, 140(6), pp.918-934.
Kumar, H., Kawai, T., and Akira, S., 2009. Toll-like receptors and innate immunity. Biochemical and biophysical research communications, 388(4), pp.621-625.
Lee, Y.B., Baskaran, P., Gomez-Deza, J., Chen, H.J., Nishimura, A.L., Smith, B.N., Troakes, C., Adachi, Y., Stepto, A., Petrucelli, L. and Gallo, J.M., 2017. C9orf72 poly GA RAN-translated protein plays a key role in amyotrophic lateral sclerosis via aggregation and toxicity. Human molecular genetics, 26(24), pp.4765-4777.
Li, W., Zhang, J., Chaoyang, Z., Hou, W., Hu, J., Feng, H. and Zheng, X., 2018. Abnormal Functional Connectivity Density in Amyotrophic Lateral Sclerosis. Frontiers in Aging Neuroscience, 10, p.215.
McGurk, L., Berson, A. and Bonini, N.M., 2015. Drosophila as an in vivo model for human neurodegenerative disease. Genetics, 201(2), pp.377-402.
Montie, H.L., and Durcan, T.M., 2013. The cell and molecular biology of neurodegenerative diseases: an overview. Frontiers in neurology, 4, p.194.
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