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Title: Rough Games and the Brain: The Structure and Function of Proteins


1
Rough Games and the BrainThe Structure and
Function of Proteins
  • Peggy Brickman
  • Department of Plant Biology
  • University of Georgia

1
2
Wrestler Chris Benoit Brains Forensic Exam
Consistent with Numerous Brain Injuries Science
Daily (Sept 6, 2007)
  • Sports Legacy Institute President, Chris
    Nowinski, a former Harvard football player and
    ex-professional wrestler, after hearing of Chris
    Benoits death, phoned Benoits father, Michael,
    with a ghoulish request to borrow the remains of
    his sons brain.
  • When Nowinski contacted me about conducting
    tests on Chris brain. I was extremely hesitant
    given the circumstances surrounding my sons
    death, said Michael Benoit.

2
3
Part I The Case of Chris Benoit
  • Twice recognized by the World Wrestling
    Entertainment as the world heavyweight champion,
    Canadian Professional Wrestler, Chris Benoit,
    was booked to win his third championship the
    weekend of his death.
  • Instead, that weekend he killed his wife and
    strangled his seven year-old son to death, and
    then hung himself using cords from a weight
    machine.
  • Medical examiners concluded that the elevated
    testosterone levels in Benoits body (probably
    prescribed to remedy deficiencies resulting after
    prior steroid abuse) did not contribute to his
    violence.
  • Nowinski believed that he did know the cause
    repetitive head injuries Benoit and other
    athletes suffer in contact sports that result in
    Chronic Traumatic Encephalophathy (CTE).

3
4
Rough Games and the Brain
  • Impact when the head slams into a hard surface,
    the skull stops abruptly, while the brain,
    floating in cerebral fluid, continues to move and
    is shaken and sometimes bruised.
  • Animation http//www.youtube.com/watch?vAmAML1-F
    2LE
  • Along with other damage, one result is that a
    nerve cell protein called ß-Amyloid Precursor
    Protein (ßAPP) is cut into pieces called
    ß-amyloid. Over time, neurofibrillary tangles
    containing tau protein fibers accumulate.

4
5
What are the functions of ß-APP, ß-amyloid and
tau?
  • Results in axon growth and signaling to other
    neurons. (ß-APP increases the levels of cell
    structure protein, actin, for example. Tau is a
    protein found with cell structure microtubules.)
  • Healing ßAPP triggers inflammatory response and
    acts as anti-coagulant to prevent blood clots.
  • May increase the expression of specific genes
    inside the cells.
  • Why would releasing ß-APP cause harm?

5
6
Benoits Brain
  • Neurofibrillary tangles (NFTs, like those seen
    below) have been found in patients suffering
    cognitive and intellectual dysfunction, including
    major depression. Similar NFTs were found in
    Chris Benoits brain.
  • Did wrestling cause his death?

6
7
Proof needed to demonstrate link
  • The Sports Legacy Institute (SLI), which oversaw
    and coordinated the testing, is an independent
    medical research organization dedicated to
    studying the long-term effects of head injuries
    in sports.
  • Most CTE occurs in boxers, but also in
    professional football players.
  • Ten percent of retired pro-football players
    suffer from depression, the same as the general
    population.
  • Before recommending drastic changes or additional
    rules for athletes, what type of evidence or
    experiments would you need to see linking
    concussions to CTE and depression?

7
8
Concussions and CTE
  • Study of more than 2,500 former NFL players by
    the Center for the Study of Retired Athletes at
    UNC found that cognitive impairment, dementia,
    and depression rose proportionately with the
    number of concussions they had sustained
    (Guskiewicz et al,. 2003, 2005, 2007). Those who
    had sustained 3 or more concussions were more
    likely to experience significant memory
    problems and 5 times more likely to develop mild
    cognitive impairment.
  • How might the NFL counter this data?

8
9
Dementia CTE and Alzheimers Disease
  • Early pathologists stained sections of an
    Alzheimers brain with iodine and saw large brown
    regions.
  • Named ß-amyloid mistaken for amylose
  • Debate Is it carb or lipid or protein?
  • What are the differences?

9
10
CQ1 Your answer should include the series of
numbers in order from the choices below.
Macromolecules are polymers composed of monomers.
For example polysaccharides like ___ are made of
the repeating monomer ___. Fats like ____ are
made of the repeating monomer ____. Proteins are
polymers made of repeating monomers called ____.
  • 1. Triglycerides 4. Nitrogen 7. Steroids
  • 2. Amino acids 5. Nucleic Acids 8.
    Cellulose
  • 3. Glucose 6. Fatty Acid 9. Phosphates

10
11
II Amino AcidsSpecific composition/comparison
with other biological molecules.
  • Tau protein tangles like those in Benoits brain
    and ß-amyloid
  • 1984 Scientists purified protein from the
    tangled fibrils seen in Alzheimers brains.
  • 1987 cloned the gene which coded for a 695 amino
    acid protein (ß-APP) which spanned the
    phospholipid bilayer.
  • ß-amyloid are fragments of the protein that are
    composed of 28 amino acids strung together.

11
12
Not all early-onset dementia comes from brain
trauma.
  • Most Alzheimers occurs in the elderly but about
    1/2 million of the 5 million people who develop
    dementia or Alzheimers each year are under 65.
    They didnt all have brain trauma, but some had a
    family history of the disease.
  • Maybe these athletes dementia was inherited (5
    of Alzheimers is caused by inherited dominant
    mutations.)
  • People with the mutation develop symptoms much
    earlier than typical (age 51).
  • Some of these mutations (15) are changes in the
    amino acids in the ß-APP protein.

12
13
Structure of Amino Acids
  • All amino acids have an amino and a carboxyl
    (acid) attached to a central carbon along with
    Hydrogen

13
14
Amino acids differ in the R group
  • 20 Different R groups Some
  • Non-polar (Hydrophobic)
  • Polar (Hydrophilic)
  • Some even contain sulfur

glutamine
14
15
Amino Acids Form Proteins
  • Condensation reactions create a covalent bond
    (Peptide Bond)
  • Forms Polypeptides
  • DNA gene mRNA
  • Primary structure

CH2OH
H
alanine
serine
glycine
H2O
H2O
15
16
Each protein has a different pattern of amino
acids
  • The R-group of each amino acid is different,
    and thus
  • imparts different qualities to the protein.
  • Hydrophilic amino acids are attracted to other
    hydrophilic
  • substances, and hydrophobic are not.

16
17
III. How Proteins DifferFunction
Structure
Protection
Metabolic Enzymes
Transport
Channels pumps
Gene Expression and Regulation
Cell Signaling (Hormones)
Movement
17
18
How Can Proteins Have Many Different Functions?
Scrabble Analogy
  • Proteins 20 amino acids
  • Glutamine
  • Isoleucine
  • Asparagine
  • Serine
  • Threonine
  • Lysine
  • Arginine
  • Carbohydrates Glucose
  • Hard to make more than one word

G1
G1
G1
G1
G1
G1
18
19
CQ2 What do proteins, lipids, and carbohydrates
all have in common?
  • A Type of reaction that links them covalently
    into large polymers of repeating monomers.
  • B Having more than a dozen monomers present in
    one polymer.
  • C Presence of the element N.
  • D Having monomers that can be either hydrophobic
    or hydrophilic.

19
20
IV. Proteins Fold into Active Shape
  • Primary Structure sequence of amino acids in
    polypeptide. For each protein (ß-APP) the
    primary structure is always identical.

Why would changing one amino acid cause the whole
protein to change shape?
21
Secondary Structure
  • Hydrogen bonds create shape.
  • http//www.stolaf.edu/people/giannini/flashanimat/
    proteins/hydrophobic20force.swf
  • Some examples of permanent structures
  • a-helix or b-pleated sheet

21
22
Tertiary Structure
  • 3D packing of polypeptides. Often involve H-bonds.

22
23
Quaternary Structure
  • Interactions between two or more polypeptide
    chains.
  • Not found in all proteins.

primary structure
amino acids
a?helix
b-sheet
secondary structure
b-sheet
tertiary structure
a?helix
quanternary structure
23
24
CQ3 Proteins such as the ß amyloid and the
mutant ß amyloid that results in early-onset
Alzheimers differ from one another because
  • Peptide bonds linking the amino acids differ from
    one protein to another.
  • The two proteins have a different combination of
    amino acids along the chain of the polypeptide.
  • Presence of the element N is only found in one
    protein.
  • The two proteins each contains their own unique
    types of amino acids.
  • The number of amino acids in the chains differ.

24
25
IV. ßAPP Proteins and Alzheimers Disease
neurons
  • ß-amyloid precursor protein (ßAPP) found in the
    phospholipid outer cell membranes of neurons.
  • ßAPP

Outside the Cell
Inside the Cell
25
26
CQ4 Which of the following amino acids might
you NOT expect to find in the intra-membrane
region of the ß-APP protein?

B
A
valine
alanine
C
D
26
aspartate
serine
27
ßAPP and Alzheimers
  • typically polypeptides are converted back into
    amino acids (by proteases) by a reaction called
    hydrolysis.
  • Also used to remove proteins when they are no
    longer needed, and to send signals.

H2O
H2O
27
28
Brain Trauma Speeds Hydrolysis
  • ß-amyloid precursor protein (ßAPP)
  • ßAPP

Outside the Cell
Inside the Cell
28
http//www.healthscout.com/animation/68/7/main.htm
l
29
CQ5 Which amino acid change in the ß-amyloid
protein fragment would be most likely to make it
stick together?
  • Replacing an amino acid with a hydrophilic
    R-group with one that is hydrophobic.
  • Replacing an amino acid with a hydrophobic
    R-group with one that is even more hydrophobic.
  • Replacing an amino acid with a hydrophobic
    R-group with one that is hydrophilic.
  • Replacing an amino acid with a hydrophilic
    R-group with one that is even more hydrophilic.

29
30
Shape and stickiness of protein dictated by amino
acids
  • Changing amino acid 717 from valine to
    phenylalanine can produce ß-amyloid that sticks
    much better to other ß-amyloid fragments and
    causes plaques to form sooner in familial
    Alzheimers.

30
31
CA6 Even if they dont have the mutation,
hard-hitting athletes may want to take some
precautions. Perhaps taking a chemical designed
to be more attractive to the basic R-groups on
ß-amyloid fragments than the fragments were to
each other thus preventing their aggregation.
Phase III trials of such a drug (Alzhemed) in
2007 failed to show benefits in 1,000 Alzheimers
patients. What kind of bonds in the ß-amyloid
protein was Alzhemed meant to disrupt?
  • Peptide bonds B. Hydrogen
    bonds
  • C. Non-polar covalent bonds D. Polar covalent
    bonds

31
32
CQ7 OK, so that drug didnt work. What do you
think the NFL should do for football players?
  1. Test for Alzheimers predisposition mutations as
    part of physicals prior to hiring.
  2. Impose mandatory rest after head injuries.
  3. Fine or fire coaches breaking the rules.
  4. Change how the game is played so that concussions
    are less likely to occur.
  5. Its just part of the game like shot knees and
    back pain. Make sure the former players have
    great health insurance that includes psychiatric
    coverage and nursing home care.

32
33
NFL and Concussions
  • Although continuing to support its policies on
    concussions and rejecting any link between
    concussions and depression CTE, NFL has several
    initiatives
  • League and players union created a fund to help
    pay medical expenses of players suffering from
    dementia.
  • New guidelines include obligatory
    neuropsychological testing, whistle-blower
    system for anonymous reports of any coachs
    attempt to override the wishes of concussed
    players or medical personnel.
  • Handheld EEGs, and functional magnetic resonance
    imaging also in testing for early diagnosis.

33
34
CQ8 You might want to know if you have a
mutation in another gene, ApoE4 that changes the
amino cysteine to arginine, and affects age of
onset of Alzheimers. How could changing the
sequence result in a change in function?
  • It could change the amount of the protein
    produced.
  • It could change the proteins 3-D shape and thus
    its ability to interact with other proteins.
  • It could change where the protein is located in
    the cell.
  • It could change the number of amino acids.

Copies of ApoE 4 mutation Average age of onset of Alzheimers
2 68
1 75
0 84
34
35
Alzheimers Prevention
  • OK. Youre not a heavy-hitting athlete and dont
    have any family history of Alzheimers, just like
    the 4.8/5 million people with Alzheimers over
    65.
  • So, theres a 10 chance youll get it by age 65,
    and a 50 chance youll get it by 85.
  • People who eat the so-called 'Mediterranean diet'
    (fruits, vegetables, bread, pasta, fish, olive
    oil and a little red wine, but low in dairy
    products and red meat) have a lower risk of
    Alzheimer's disease. So do people who exercise
    regularly, use (not lose) their minds, and have
    been taking non-steroidal anti-inflammatories
    like aspirin for least two years.

35
36
Interested in Reading More?
  • Scientific American http//www.scientificamerican
    .com has a great set of articles on the latest
    research, including one in March 2009 on prions
    and Alzheimers.
  • Articles
  • Medline search http//www.nlm.nih.gov/medlineplus/
    alzheimersdisease.html
  • Lobo, I. (2008) Epistasis Gene interaction and
    the phenotypic expression of complex diseases
    like Alzheimer's. Nature Education 1(1)
  • McKee et. al. (2009) Chronic Traumatic
    Encephalopathy in Athletes Progressive Tauopathy
    After Repetitive Head Injury. J. Neuropathol Exp
    Neurol.

37
Image Credits
  • Slide 3
  • Description Photo of Chris Benoit.
  • Source From Wikimedia Commons, by dani nuestro
    from Bangkok, http//commons.wikimedia.org/wiki/Fi
    leBenoitInTheRing.jpg
  • Clearance Creative Commons Attribution-Share
    Alike 3.0 Unported License(CC BY-SA 3.0).
  • Slide 4
  • Description Concussion illustration.
  • Source Adapted from Wikimedia Commons,
    http//commons.wikimedia.org/wiki/FileConcussion_
    Anatomy.png, original by Max Andrews.
  • Clearance Used in accordance with the Creative
    Commons Attribution-Share Alike 3.0 Unported
    license.
  • Slide 6
  • Description Neurofibrillary tangles in the
    Hippocampus of an old person with
    Alzheimer-related pathology.
  • Source Wikimedia Commons, http//commons.wikimedi
    a.org/wiki/FileNeurofibrillary_tangles_in_the_Hip
    pocampus_of_an_old_person_with_Alzheimer-related_p
    athology,_Gallyas_silver_stain.JPG, by Patho.
  • Clearance Used in accordance with the Creative
    Commons Attribution-Share Alike 3.0 Unported
    license.
  • Slide 9
  • Description Illustration comparing healthy brain
    and Alzheimers brain.
  • Source Alzheimers Association,
    http//www.alz.org/brain/09.asp
  • Clearance Used with permission.

38
  • Slide 11
  • Description Illustration of plaques.
  • Source Alzheimers Association,
    http//www.alz.org/brain/11.asp
  • Clearance Used with permission
  • Slide 18
  • Description Scrabble analogy for the greater
    complexity of proteins due to the greater number
    and type of monomers.
  • Source Peggy Brickman, adapted from Nutrition
    Insel, Turner, and Ross.
  • Slides 21-23
  • Description Illustration of four levels of
    protein structure.
  • Source Wikimedia Commons, http//commons.wikimedi
    a.org/wiki/ImageProteïen_struktuur.png.
  • Clearance Used in accordance with the Creative
    Commons Attribution-Share Alike 3.0 Unported
    license.
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