Disease causing protein of Alzheimers diseaseUniversity of Toronto ScarboroughProfessor Shelley bruntBiochemistry I: Proteins and Enzymes: bioc12hZhi Xin Huang1003348424
Protein misfolding disease (PMD)Christian Anfinsen demonstrated that protein conformations form accordingly based by their primary amino acid sequence It is understood that mutant proteins may be more susceptible to protein misfolding (Zhang et al., 2004)However, wild-strain proteins adopting native conformation in some individuals and misfolding in other individuals under similar environmental condition remains elusive (Zhang et al., 2004)Diseases associated with the misfolding of proteins accumulate in tissues and generally organize themselves in ?-sheet structures (Moreno-Gonzalez et al., 2017)Aggregation of different protein components results in different diseases: Alzheimers Disease: Amyloid-beta (A?) and hyperphosphorylated tau (ptau) Parkinsons disease: alpha-synuclein (?-syn) Type 2 Diabetes: islet amyloid polypeptide (IAPP) (Moreno-Gonzalez et al., 2017)
Alzheimers disease (aD)Alzheimers disease a disease that has no curative treatments available is thought to be the main causes of dementia in the 21st century (Scheltens et al., 2016)It is greatly understood by researchers to be the accumulation of both amyloid and tau (Scheltens et al., 2016)Alzheimers disease is currently under exponential growth where prevalent cases of AD after the age of 65 doubles consistently every 5 years (Forloni et al., 2002)Percentage of inheritance of AD ranges from 1% to 30% Inheritance of ?4 of apolipoprotein E is a major biomarker for the risk of developing AD (Forloni et al., 2002)TREATMENT: Currently there are four treatment drugs for dementia offered to patients diagnosed with ADAcetylcholinesterase inhibitorsRivastigmineGalantamineGlutamate antagonist memantineAll treatment drugs are used for stabilizing daily cognitive functions for moderate dementiaHowever, clinical researchers are looking to develop new treatment drugs to prevent early symptoms of Alzheimers disease and accumulation of ?-amyloid proteins (A?) and hyperphosphorylated tau (Scheltens et al., 2016)
AD pathology and ?-amyloid deposits Alzheimers disease pathogenesis is greatly understood to be caused by aggregation of ?-amyloid proteins (A?) and hyperphosphorylated tau The native configuration of A? is an unstable soluble ?-helix whereby misfolding causes a number of tertiary intermediates In its final quaternary structure is an insoluble fibrillar ?-sheet known as A?Formation of ?-helix amyloid to A? results in insoluble accumulation of amyloid deposits which is generally the onset of early Alzheimers disease
Genetic mutations present in fad patients Forloni et al. conducted an experiment to study the role of misfolded protein and its association to ADThe genomic DNA was extracted from 70 patients suffering from AD to identify the presence of different coding mutationsCase 1: exhibit a classical progression of AD where a substitution of leucine to phenylalanine was present at codon 219Case 3: is the result of a missense mutation at codon 392 where the patient exhibited a 3 year history of aggressive AD symptoms This experiment confirms that Alzheimers disease is the caused of a variable amount of genetic mutations that still remains elusive (Forloni et al., 2002)Table 1. Genomic Mutation identified from 70 patients suffering from AD (Forloni et al., 2002 )
Alzheimers disease induced by misfolding of another protein Diseases could be due to the misfold of more than just one protein A study done by Moreno-Gonzalez et al. examined the overlap of protein misfolding in correlation to the existence of different pathologies Similarities were found with patients suffering from type 2 diabetes (T2D) where accumulation of A? and ptau was found in their pancreaslikewise, accumulation of IAPP was found in the cerebral of patients suffering from ADThis lead to the hypothesis that aggregation of one misfolded protein may trigger the misfold of another It was apparent that with existing aggregation of IAPP this could then induce the cross-seeding A? deposits in the brain(Moreno-Gonzalez et al., 2017)Figure 1. In vitro done to examine the aggregation of A? in the presence of IAPP. The figure was set up to compare amyloid formation through thioflavin T on the y-axis in respect to time (h) on the x-axis. A control no seed was used to compare A?40 seed and IAPP seed. Presence of A?40 seed exhibit a maximum aggregation at ~96h whereas presence of IAPP showed a maximum aggregation at ~144h. (Moreno-Gonzalez et al., 2017).
conclusionAlzheimers disease is the leading contributor to causing dementia at an increase rate Aggregation of ?-amyloid proteins (A?) and hyperphosphorylated tau have been extensively studied as well as compared to other pathologies such as patients suffering from type 2 diabetes Research in AD is making rapid advancements in the development of drugs that could potentially be used for early symptoms of AD Researchers are currently working on making a cocktail of anti-amyloid and anti-tau treatment to supress the aggregation of both mutation proteins Current drugs may be used to target dementia enhancing daily cognitive functions
References Forloni, G., Terreni, L., Bertani, I., Fogliarino, S., Invernizzi, R., Assini, A., . . . Bertoli, A. (2002). Protein misfolding in Alzheimers and Parkinsons disease: Genetics and molecular mechanisms. Neurobiology of Aging, 23(5), 957-976. doi:10.1016/S0197-4580(02)00076-3Moreno-Gonzalez, I., Iii, G. E., Salvadores, N., Shahnawaz, M., Diaz-Espinoza, R., & Soto, C. (2017). Molecular interaction between type 2 diabetes and Alzheimers disease through cross-seeding of protein misfolding. Molecular Psychiatry,22(9), 1327-1334. doi:10.1038/mp.2016.230Scheltens, P., Blennow, K., Breteler, M. M. B., de Strooper, B., Frisoni, G. B., Salloway, S., & Van der Flier, W. M. (2016). Alzheimer’s disease. The Lancet, 388(10043), 505-517. doi:10.1016/S0140-6736(15)01124-1Zhang, Q., Powers, E. T., Nieva, J., Huff, M. E., Dendle, M. A., Bieschke, J., Kelly, J. W. (2004). Metabolite- initiated protein misfolding may trigger Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 101(14), 47524757. doi:10.1073/pnas.0400924101