Neurodegenerative Diseases: Causes, Symptoms And Treatment

Proteins and its Folding

Write an essay on Neurodegenerative Diseases.

Neurodegenerative diseases are chronic and fatal illnesses that affect most of activities of human being. This group includes diseases like Alzheimer's, Parkinson', huntington's and CZJ disease etc. Most of neurodegenerative disease in humans is caused by protein misfolding and aggregation.

Proteins and its folding:

Proteins are the molecules which control our most vital cellular functions in the human body. To function properly, a protein must first fold into its stable three-dimensional structure, sometimes tertiary and quaternary conformations (Dill and MacCallum, 2012). Fig 1A.

Figure 1A: 3-D Showing structure of folded protein.

Protein composed of mainly 100-600 amino acids in the polypepetide chain. To decrease size of folded, large protein are divided into domains which are fold seperately. Inside of cell, structure is complex and it contained proteins and other macromolecules (Christopher M., 2004). The mechanics behind folding process is thermodynamically driven by hydrophobic effect. As water removes from one amino acid, while reacting with another and forms a hydrophobic core, as hydrophilic site of amino acids remain at the surface. Thus, bigger size protein collapse into a globular structure, which results in reduction of conformation (Figure 1B). During rearrangement  step correct amino acid are attached which form protein with most stable and biologically active conformation. Additional factors are responsible witjin the cell which assist in the folding process, folding catalysts and molecular chaperones (Hartl U., 2010).

Figure 1B: Showing compaction of protein.

To make biologically active, protein need unique 3-D structure which is acquired by the folding process. A small mistake while folding process, resulted in misfolding of protein structure, which can be dangerous. However, inside the cell, conditions are highly sticky, therefore there is problem in folding protein by themselves and requires additional help from special kind of protein called chaperons (Tapan K., 2006).

Molecular chaperons assist other protein to achieve active 3-D conformation, this preventing misfolding and aggregation of protein during folding, thus increasing the folding efficiency and decreases  unwanted intermediated which lead to damaged protein (e.g. aggregation).

Protein sometimes cannot achieve stable state, due to occurrence of mutation in the amino acid sequence or may be due to error in folding step. This proteins are further called as misfolded protein because they went through degradation pathways. This type of proteins go through quality control system, which formed from molecular chaperons and ubiquitin proteasome system (Berke SJS., 2003).

Quality control system plays a crucial role in the function and survival of cell. A class of chaperone is calnexin, forms a part of quality control system, which recognises abnormal folded proteins and removes distorted protein. Some class of quality control chaperone associated with the endoplasmic reticulum (ER), e.g. calnexin and calreticulin, BiP and ERp 57 (Swanton E., 2003), which detect misfolded protein and retain them in endoplasmic reticulum and allow only correct protein to reach the cytosol. (Welch WJ., 2003).

Ubiquitin proteasome pathway is important part of quality control in the cell. Disturbance in the UPP, caused misfold in the protein structure in the endoplasmic reticulum and thus function of enzyme is lost due to ubiquitin conjugation and deconjugation pathway. This alter the ubiquitin proteasome pathway and results in aggregation of protein in the cell. Aggregated protein forms an amyloid-like structure, which is a serious cause of different types of degenerative diseases (Berke SJS., 2003 and Tapan K., 2006).

Chaperones

Protein misfolding and aggregation is an important problem. During synthesis of protein, when protein fails to folds correctly, protein lost its biological function. This happened because of mutation in the amino acid sequence. The disease related to this problem are cystic fibrosis, Alzheimer's disease, p53 cancer and Parkinson's disease (table no. 1).

Table no. 1: Showing various diseases related to protein misfolding and aggregation.

Protein misfolding disorders occurs because of mutation in the polypeptide chain. Misfolded protein caused loss of biological function in cystic fibrosis or harmful gain in function as in neurodegenerative disease. Proteins aggregates sometimes converted into fibrilliar structure contain with plenty of H bonds, which is insoluble. These protein aggregates are known as amyloids and its deposition is in plaque like structure form.

From last two decades, protein misfolding is research topic for most of the researchers. As according to Susan Lindquist, protein misfolding is related to many half of the human disease, e.g. P53 mediated cancer also related to misfolding protein. Many cancers and protein folding diseases are due to mutation in protein. Structural changes causes aggregation of protein, thus result in toxicity and cell death.

According to chaperone overload hypothesis, with aging, misfolded proteins gets accumulated that prevents molecular chaperone to repair mutation in the polypeptide chain, which might causes disease. According to study, result showed that yield of stable protein from refolding is low, as intermediates forms between folding reaction (Csermely P., 2001). These stable folded intermediates are known as off pathway intermediates, which forms insoluble aggregates, that may be a serious cause of different degenerative diseases. Main cause of most protein conformation disease is formation of aggregates caused by destability in alpha helical structure and side by side formation of beta sheets. Beta sheet forms between alternative peptide strands. Peptide strands are linked by H bond between aligned pleated structure. Thus, pleated strand linked to another with beta linkage. This beta linkage are donor sites which bind to pleated sheet and beta sheet of next is acceptor site (Fig. 2) (Tapan K., 2006).

Figure 2: showing amyloid formation.

Chronic and progressive neurodegenerative disorders are characterised by loss of neurons in motor and sensory area.  Occurrence of brain lesions is most common feature among neurodegenerative disorders, which are formed by the accumulation of misfolded or aggregated proteins. Some of the examples related to aggregation are, Alzheimer's disease which is neurodegenerative disorder of brain in elders, which causes impaired behaviour and loss of memory. This occurs due to Aβ and fibilliar tangles deposition in the extracellular areas of the brain. This Aβ proteins deposit in the hippocampus, disturbing neural network and results in cell death and memory loss. These aggregates are called as amyloids. They are formed from small, mild mis folded protein called soluble oligomers and is highly toxic misfolded protein (fig. 3) (Hartl U., 2010).

Figure 3: Showing cross section of normal and Alzheimer’s brain.

In Parkinson;'s disease protein gets collected in the intracellular spaces. It is characterised by muscle rigidity, posture instability and tremors while resting. The main cause of heredity disorder is mutation (Fig. 4). In variant Creutzfeldt-Jacob syndrome disease may be because of conformation change from alpha helix wild protein PrP^c gene to beta sheet dominant PrP^Sc gene, which lead to protein misfolding and aggregation.

Protein Misfolding Disorders

Figure 4: Structure of amyloid fibrils deposited in the neurons in parkinson's disease.

α1- antitrypsin deficiency main reason is mutation, this is done by single base pair substitution (Gul342-Lys) in the gene. Protein misfolding during synthesis of protein, initiated polymerisation reaction, this lead to protein aggregates with in the cell. α1- antitrypsin (serpin) is a proteolytic inhibitor enzyme with serine amino acid in its active site, binds to proteinase target molecule and and caused conformation changes in the molecule. Therefore, there is an aggregation of protein, which occurred through beta sheet interaction with another serpin molecule. The beta strands blocker prevent this aggregation of proteins.

The p53 cancer is also example of misfolding disorders. P53 is a tumor suppressor protein, also called as sequence specific transcription factor, which maintain genomic integrity. It occurs through mutation in the gene. In normal condition, p53 levels are low, but after mutation when DNA gets damage, the levels of p53 rises. The function of p53 is that, it binds to regulatory sites, and starts producing protein that stops cell division and this keeps on working until, the damaged DNA gets repaired. If damaged is severe than, it initiates programmed cell death or apoptosis, thus completely removal of damaged DNA. When mutation occurs, it loses it biological function and caused cancer ((Tapan K., 2006).

Reference:

1. Agorogiannis EI. (2004). Protein misfolding in neurodegenerative diseases. Neuropathol Appl Neurobiol. 30(3):215-24.

2. Berke SJS. (2003). Protein aggregation and the ubiquitin proteasome pathway: gaining the UPPer hand on neurodegeneration. Curr Opin Genet Dev. 13: 253-261.

3. Chaudhuri TK, Paul S. (2006). Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS J. 273(7):1331-49.

4. Christopher M. (2004). Principles of protein folding, misfolding and aggregation. Seminars in Cell & Developmental Biology. 15: 3-16.

5. Csermely P. (2001). Chaperone overload is a possible contributor to ‘civilization diseases'. Trends Genet. 17: 701-704.

6. Dill K. A., MacCallum J. L. (2012). The protein-folding problem, 50 years on. Science 338, 1042-1046.

7. Ellis RJ & Pinheiro TJ (2002) Danger - misfolding proteins. Nature. 416: 483-484.

8. Gao X. (2008). Quality control of the proteins associated with neurodegenerative diseases. Acta Biochim Biophys Sin. 40(7):612-8.

9. Gomes CM. (2012). Protein misfolding in disease and small molecule therapies. Curr Top Med Chem. 12(22):2460-9.

10. Hartl U. (2010). file:///C:/Users/Kalpana%20Singh/Desktop/bm10_Proteinfolding-basetext.pdf.

11. Hartl FU. (2011). Molecular chaperones in protein folding and proteostasis. Nature. 475(7356):324-32.

12. Julie S. (2014). Mechanisms of protein-folding diseases at a glance. Dis Model Mech. 7(1): 9-14.

13. Muchowski PJ. (2002). Protein misfolding, amyloid formation, and neurodegeneration: a critical role for molecular chaperones. Neuron. 35(1). Pp. 9-12.

14. Pietzsch J. The importance of protein folding. https://www.nature.com/horizon/proteinfolding/background/importance.html.

15. Protein Folds and Protein Fold Classification. https://www.proteinstructures.com/Structure/Structure/protein-fold.html.

16. Protein Folding and Processing. The Cell: A Molecular Approach. 2nd edition. https://www.ncbi.nlm.nih.gov/books/NBK9843/.

17. Soto C. (2003). Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 4. Pp. 49-60.

18. Soto C. (2013). Protein Misfolding in Neurodegenerative Diseases. Journal of Neurology & Translational Neuroscience. https://www.jscimedcentral.com/Neuroscience/Articles/neuroscience-1-1010.pdf.

19. Swanton E. (2003). Role of calnexin in the glycan-independent quality control of proteolipid protein. EMBO J. 22: 2948-2958.

20. Tapan K. (2006). Protein-misfolding diseases and chaperone-based therapeutic approaches. FEBS Journal. 273: 1331-1349.

21. Welch WJ. (2003). Role of quality control pathways in human diseases involving protein misfolding. Semin Cell Dev Biol. 15: 31-38.