Proteopathic Diseases and Amelogenesis Imperfecta Flashcards

(50 cards)

1
Q

Define Proteopathy

A

a class of diseases where proteins become structurally abnormal and disrupt the functions of cells, tissues and organs of the body

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2
Q

What happens if the Proteins Mutate and Misfold?

A
  • become toxic and lose normal function
  • accumulate in the cell
  • damage the tissues
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3
Q

How does Amelogenesis Happen?

A
  • mutation on the amelogenin gene = Y64H
  • leads to dysfunctional protein
  • aggregation of the protein
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4
Q

What are the Secretory Cells of the Enamel?

A

ameloblasts

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5
Q

How are Ameloblasts formed? 2 Paths

A
  • gene transcribed onto mRNA
    TWO PATHS:

1) attach onto free ribosome in the cytoplasm
- protein constructed and used with the cells

2) attach onto fixed ribosome on the RER
- protein folds into 3D shape
- modified and package into vesicles
- transport to golgi apparatus
- enzymes modify protein and glycoprotein
- released into the extraceullar environment

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6
Q

What are Multiple Vesicles Called?

A

Cistamae

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7
Q

What are the 3 Different Types of Vesicles?

A

Lysosome - digestive enzymes
Secretory - empty products outside cell by exocytosis
Membrane - add new lipids and proteins to plasma membrane

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8
Q

What are the Two Different Pathways which Proteins Translocate to the Endoplasmic Reticulum

A

Co-translational translocation
Post-translational translocation

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9
Q

Describe Co-translational translocation

A
  • during translation
  • ribosome attaches onto the ER
  • protein is inserted into the ER membrane
  • protein gets translated
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10
Q

Describe Post-translational translocation

A
  • after translation
  • signal sequence
  • protein is released from the ribosome
  • protein is inserted and translocated into the rough endoplasmic reticulum
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11
Q

What does a Polypeptide Chain Develop into?

A

3D structure
- either alpha helices or beta pleated sheets

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12
Q

3 Descriptions of the Folding of Protiens

A

randomised
occurs in an aqueous solution
depends on the side chains

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13
Q

What is an Important Protein which Reduces the Error of Misfolding?

A

chaperone = BiP

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14
Q

2 Ways in Which Disrupted Protein Folding can Occur.

A

Mutation
Faulty Phosphorylated Modification

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15
Q

How can a Misfolded Protein lead to Disease? (5)

A
  • accumulates
  • forms inclusion bodies, fibres
  • ER stress
  • tissue dysfunction
  • disease
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16
Q

What happens when you get ER Stress?

A

= unfolded protein response

  • cell activates complementary adaptive mechanisms
  • eliminates damaged cells by apoptosis
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17
Q

Why don’t we Constantly get ER Stress?

A

UPR - unfolded protein response
- identifies the faulty proteins

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18
Q

What is the Mechanism of UPR?

A

to produce transcription regulatory proteins such as BIP
- receive signal to be induced from transmembrane sensors

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19
Q

How does BIP Help Fold Proteins Correctly?

A
  • regulate transmembrane sensors in the ER membrane and on the cytoplasmic side
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20
Q

Give 3 Transmembrane Sensors, which BIP regulates

A

IRE1, PERK and ATF6

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21
Q

How does BIP Regulate IRE1

A
  • two protein kinases phosphorylate due to misfolded protein
  • induces ribonuclease domain
    = splice a specific mRNA
  • activates specific transcription regulatory proteins
22
Q

How does BIP Regulate PERK

A
  • two protein kinases phosphorylate due to misfolded protein
  • activates translation initiation factors
  • forms specific transcription factors - increase genes for folding
23
Q

What is the Role of Translation Initiation Factors in PERK?

A
  • reduce synthetic rate of protein translocation
  • less ER stress
24
Q

How does BIP Regulate ATF6?

A
  • ATF6 moves to golgi apparatus
  • proteolytic cleavage of the cytosolic domain
  • activates genes specific to UPR
  • reduce ER stress
25
3 Things Which can Happen After UPR.
ERAD - protein degradation CHOP - apoptosis genes activate to increase protein folding capacity
26
What is the Prevalence of AI?
1/700-1400
27
Define Genesis Imperfecta, where does it originate
a group of developmental conditions in the genome.
28
Clinical Phenotypes of AI
- hypoplastic enamel - thin or absent - hypomaturation - name is normal thickness but white surface - mistaken for fluorosis - hypermineralized
29
When do you know you have AI?
when teeth are erupted
30
Symptoms and Treatment of AI.
- sensitivity - discolouration - prone to disintegration - can only be managed
31
Describe the 5 Stages of Enamel Formation
Presecretory Secretory - 30% mineral - initial mineral and matrix - complete when full thickness of tissue is layed - ameloblasts = tall, columnar, densely packed, 7mm height Transition - at or during amelogenin secretion Early Maturation - 40% mineral Maturation - 90% mineral - final matrix removal - final mineral content acquired - ameloblasts = shorted to half and nucleus at centre - final mineralisation is considered complete post-eruption
32
What do we use to Study AI?
mice showing enamel defects
33
How do we study AI? What is the Project.
Mutagenesis Project - induce the mutation in male rodent using chemical 'N-Ethyl-N-Nitrosourea' (ENU) - cross bred with healthy mice - search for abnormalities
34
What is the Allele for the Phenotype known as?
wild-type
35
Define Monophyodont
having one set of teeth - lab mice
36
Describe the Enamel of Mice.
single crystal of hydroxyapatite - rods within are rhombohedral, 25-50nm - 10^4 Bundle into larger nanorods inner enamel - nanorods are arranged in intersecting sections outer enamel - nanorods are parallel = makes the edge of enamel detachable and sharp = resistant to acid wear
37
In Mice's genes, where is the Amelogenin allele?
on the X chromosome women = XX men = XY
38
What is the Amelogenin Mutation?
Y64H
39
In Humans Genes, where is the Amelogenin allele?
on X and Y women = XX men = XY
40
Which gene produces Amelogenin?
Amex
41
Define Homozygous.
having two identical alleles of the gene
42
Define Heterozygous.
having two different alleles of a gene
43
How does Enamel Differ in Beavers?
more iron, more strength
44
How do Mutations Affect the Stages of Enamel?
Secretory and Maturation - more secondary ameloblasts Transition and Maturation - ameloblast contact with enamel matrix is occasionally lost = blister like structure
45
What is the Effect of Mutation on the Enamel?
- tomes process is absent = disorganised vascular pattern - loss of normal ER and golgi structures - nuclei of ameloblasts become distorted
46
How can you Measure if Mutant Amelogenins are being Secreted?
Western Blotting Analysis
47
Describe Western Blotting Analysis
- detect a specific protein - using gel electrophoresis to separate
48
When Mutant Amelogenin Accumulates in the ER, does it cause ER Stress and Activation of UPR?
- evidence needs to be found - perform in-situ-hybridization and quantitive real time PCR
49
Does ER stress Lead to AI?
Yes
50
What can be used to Manage ER Stress when it leads to AI?
4-phenylbuturate - used for urea cycle disorders - shows improvement in incisors and recovery of enamel