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Protein misfolding in Alzheimer's disease

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Presentation on theme: "Protein misfolding in Alzheimer's disease"— Presentation transcript:

1 Protein misfolding in Alzheimer's disease

2 Classify Alzheimer as one of several types of dementia.
Explore the symptoms and signs of Alzheimer’s disease. Understand the biochemical basis of Alzheimer. List other protein misfolding disorders. Recognize the mechanism of protein folding. Describe the physical and chemical changes due to protein denaturation.

3 Mrs. Nadia, a 78-year-old female, has been a resident of EL-Yasmeen Assisted Living house for about two years. Her husband initially admitted her because of memory decline, and progressive need for assistance with activities of daily living that could not be met by her family.

4 What are the chief presenting complaints ?
memory decline progressive need for assistance with activities of daily living

5 How will you analyse the causes of the presenting complaints?
Alzheimer's disease Most common form of dementia progressive, degenerative disease that causes changes in brain tissue resulting in impaired memory, thinking and behavior

6 Extended Modular Program
Video Extended Modular Program

7 What changes occur in the brain with Alzheimer's disease?
Loss of brain cells ♦ Shrinking of brain size There is accumulation of abnormally folded protein in the brain ♦ "Plaques" and "tangles" develop in nerve cells of brain - Nerve fibers separate ♦ Production of chemical messengers ("neurotransmitters") is reduced - "Signals" can no longer pass from one nerve cell to another ♦ Cells eventually die

8 What is the biochemical basis of Alzheimer

9 Caused by different gene mutations Lead to abnormal protein folding.
Alzheimer Disease Caused by different gene mutations Lead to abnormal protein folding.

10 Alzheimer Disease There is accumulation of abnormally folded protein in the brain ,called amyloid precursor protein (APP) which is critical to neuron growth, survival and post-injury repair. This misfolded protein will then be degraded into smaller fragments called beta-amyloid which form plaques around neurons.

11

12 Mechanism of action of chaperones
Correctly folded protein Polypeptide Steps of Chaperonin Action: An unfolded poly- peptide enters the cylinder from one end. The cap attaches, causing the cylinder to change shape in such a way that it creates a hydrophilic environment for the folding of the polypeptide. The cap comes off, and the properly folded protein is released.

13 Protein misfolding The folding control system is not perfect and sometimes occur improperly.

14 Normally Diseases Effects:
misfolded proteins are usually degraded inside the cell or even refolded. Normally Deposits of misfolded proteins accumulated inside and outside of the cells, protein deposits(amyloid), resulting in diseases. Diseases

15 List Examples of protein misfolding disorders
amyloidosis Alzheimer disease prion diseases α1-antitrypsin deficiency. Cystic fibrosis

16 Defect in folding of the protein result in which of the following disease  
a) Alzheimer b) Migraine c) Parkinsonism  d) Depression

17 Which of the following group of proteins assist in the folding of other proteins?
a) Proteases b) Proteosomes c) Templates d) Chaperones

18 Extended Modular Program
How is Cystine formed based on the shown diagram? reduction condensation hydrolysis hydration oxidation What is the type of bond in the red circle in the diagram? covalent bond disulphide bond ionic bond polar covalent bond metallic bond Extended Modular Program

19 Inter chain disulfide bond
REDUCTION S SH S SH OXIDATION Cystine 2H

20 Extended Modular Program
Complete There are four leveles of protein structure: __________________________ 2) __________________________ 3) __________________________ 4) __________________________ There are two common types of secondary structures,   Primary structure Secondary Structure Tertiary structure Quaternary structure (α helix) and (β sheet). Extended Modular Program

21 Levels of Proteins Structure
Taken from Lehninger, Principles of Biochemistry, 3rd Edition

22 Extended Modular Program
This type of cross link in a tertiary structure is known as A hydrogen bond an ionic bond a hydrophobic attraction a peptide bond a Extended Modular Program

23 Which one of the following is not a feature of the alpha helix?
a) It is one of the most important secondary structure. b) R groups protrude outside alpha helix c) All hydrogen bonds are aligned in the same direction. d) Long stretches of left handed -helices occur in proteins.

24 Alpha helix and Beta pleated sheet are examples of
a) Primary structure b) Secondary structure c) Tertiary structure d) Quaternary structure

25 Compare alpha helix and beta pleated sheet
coiled Shape 3.6 amino acids/turn No of amino acids Intra-chain hydrogen bond Stabilized by One polypeptide chain Yes Disruption by proline Myoglobin ,hemoglobin Examples

26 The structural proteins are involved in maintaining the shape of a cell .The shape of these proteins is a) Globular b) Fibrous c) Stretch of beads d) Planar

27 Classification according to shape
Fibrous Proteins Globular Proteins Axial ratio More than 10 Not more than 4 i.e. the protein is compact and coiled Solubility Water insoluble Mostly water soluble Examples Structural proteins (Scleroproteins) e.g. Collagen, elastin, and - keratin Dynamic proteins e.g. Insulin, albumin, globulins, and enzymes.

28 Proteins sometimes associate to form homo or hetero- dimers
Proteins sometimes associate to form homo or hetero- dimers. Which one of the following refers to this associated form? a) Denatured state b) Molecular aggregation c) Precipitation d) Quaternary structure

29 True or false; comment The hydrophilic/hydrophobic character of amino acid residues is important to secondary structure. An octapeptide composed of four peptide bonds. the individual polypeptide chains are usually bound to one another by disulfide bond. Proline is an amino acid that does not form an α-helix. F F F T

30 Protein denaturation

31 Exertional heat illness
as July 20 in Luxor and the fourth straight day that would have a high temperature above 40°C. Ahmed was running and decided to stop by his mother's house. Ahmed's mother, Mona, was eighty-four years old. She was able to keep up with her housekeeping and still care for her small garden. When Ahmed reached his mother's house, he found his mother unconscious, Feverish, profuse sweating, dry skin and rapid pulse. All of the windows in the house were closed. The emergency services operator instructed Ahmed to apply cold wash cloths to her mother's forehead and face and if possible to position his mother in front of a fan while using a spray bottle to spray tepid water on her skin.

32 When the paramedics arrived ,they informed Ahmed that his mother had suffered heat stroke. Mona was making rapid progress to recovery but was being given fluids and electrolytes intravenously and was going to stay in the hospital overnight for observation.

33 Key points as July 20 in Luxor and the fourth straight day that would have a high temperature above 40°C. Ahmed was running and decided to stop by his mother's house. Ahmed's mother, Mona, was eighty-four years old. She was able to keep up with her housekeeping and still care for her small garden in her backyard. When Ahmed reached his mother's house, he found his mother unconscious, feverish, profuse sweating, dry skin and rapid pulse. All of the windows in the house were closed. The emergency services operator instructed Ahmed to apply cold wash cloths to her mother's forehead and face and if possible to position his mother in front of a fan while using a spray bottle to spray tepid water on her skin. When the paramedics arrived ,they informed Ahmed that his mother had suffered heat stroke. Mona was making rapid progress to recovery but was being given fluids and electrolytes intravenously and was going to stay in the hospital overnight for observation.

34 What are the chief presenting complaints ?
Unconscious Feverish profuse sweating dry skin rapid pulse The diagnosis of heatstroke rests on two critical factors: hyperthermia and central nervous system dysfunction.

35 What are the chief risk factors in this case?
HOT dry weather(Luxor, July) Old age Work in garden

36 How will you analyse the causes of the presenting complaints?
Heat stroke, also known as sun stroke, is a severe heat illness, defined as hyperthermia with a body temperature greater than 40.6 °C (105.1 °F) because of environmental heat exposure with lack of thermoregulation. Heat -> denatured proteins / cytotoxicity - Increased release of toxic metabolites - End-organ damage

37 ''It does not take long either to boil an egg or to cook neuron'‘ Validate this statement
High heat cooks the sensitive tissues of the brain, denaturing proteins and disrupting communications.

38 Video

39 Heat Stroke Lessons Learned:
Heat stroke is a life threatening emergency. Heat stroke is more common in elderly, military solider, children. Heat stroke involves hyperthermia and CNS changes, with a risk of multi-organ failure Try to cool these people down as quickly as possible

40 Protein denaturation

41 Denaturation of proteins
It is not accompanied by hydrolysis of peptide bonds. The protein becomes formed of random coils It results in the unfolding and loss of the protein’s secondary and tertiary structure. The loss of the native ‘biologically relevant’ conformation of the protein.

42 Denaturation of Proteins
Denaturation is a process that disrupts secondary, tertiary, and quaternary structures. The primary structure is not destroyed during denaturation.

43 Which of these statements regarding
the process illustrated in this photo is false? A. The three-dimensional shape of the protein is altered B. The proteins are being denatured by heat C. The protein denaturation is reversible D. The protein loses its function

44 Name the chaotrope in the above experiment and state the role of the chaotrope.
Mercaptoethanol; disrupts the hydrogen bonds in the protein structure Urea; disrupts the hydrogen bonds in the protein structure Mercaptoethanol; disrupts the hydrophobic interactions in the protein structure Urea; disrupts the hydrophobic interaction in the protein structure Mercaptoethanol; reduces the disulphide bond in the protein structure

45 Structural-transport, defense, catalysis
Complete Structural-transport, defense, catalysis In a dipeptide, two amino acids bond to each other via a(n) _____ reaction . Name the four most common functions of proteins in living organisms High biological value proteins are found in _____. _____ , _____and _____ are examples of lipoproteins Condensation Animal proteins, beans LDL-HDL, VLDL

46 Many amino acids joined together
= Polypeptide chain N-terminus C-terminus H H O H H O H H O H H O H H O H H O H H O H H O H N C C N C C N C C N C C N C C N C C N C C N C C OH H CH3 CH2 CH2 CH2 CH CH2 CH2 OH C OH H3C CH3 SH O Figure: 3.9b Caption: (b) Amino acids can be linked into long chains by peptide bonds.  OH

47 NOTE Dipeptide Tripeptide Two amino acids Single peptide bond
Three amino acids Two peptide bonds

48 Use the pictured reaction below to answer the following questions.
Identify functional group Q on compound (a). _______________ Identify functional group P on compound (a). Identify the monomer represented by compound (a). Identify compound (b). _______________ Identify the type of reaction that would produce (b). ______________ Name the bond formed at the arrow R above _______________ Carboxyl group Amino group Amino acid Dipeptide Dehydration Peptide bond

49 Extended Modular Program
In the tetrapeptide Gly-Gln-Tyr-Lys, the C-terminal amino acid is A) Gly B) Gln C) Tyr D) Lys Extended Modular Program

50 Which one of the following bio molecules is insoluble in water?
α‐keratin Hemoglobin Ribonuclease Adenine


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