TSE SE present presented ed by by Himadri Himadri & M - - PowerPoint PPT Presentation

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TSE SE present presented ed by by Himadri Himadri & M - - PowerPoint PPT Presentation

Sep 10, 2022 331 likes •820 views

TSE SE present presented ed by by Himadri Himadri & M & Markus kus Source: Markus Gerstel, 2008, Balliol College TSE OMG we are all going to die!!!11 Transmissible Spongiform Encephalopathy An expedition into death,

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SLIDE 1

TSE SE

present presented ed by by

Himadri Himadri & M & Markus kus

Source: Markus Gerstel, 2008, Balliol College
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SLIDE 2

TSE

”OMG we are all going to die!!!11”

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SLIDE 3

Transmissible Spongiform Encephalopathy

An expedition into death, depression, and zombies

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SLIDE 4

Taxonomy

Protein Misfolding Diseases Proteopathies Alzheimers Amyloid β peptide ALS

Superoxide dismutase

Cystic Fibrosis

Cftr

Huntinton's Disease

Huntingtin

TSE

Prion diseases

Source: Soto, 2006, Prions, the new biology of proteins, table 11.1
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SLIDE 5

Taxonomy

Protein Misfolding Diseases Proteopathies Alzheimers Amyloid β peptide ALS

Superoxide dismutase

Cystic Fibrosis

Cftr

Huntinton's Disease

Huntingtin

TSE

Prion diseases

Source: Soto, 2006, Prions, the new biology of proteins, table 11.1
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SLIDE 6

scrapie sheep CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Transmissible Spongiform Encephalopathy Prion diseases

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SLIDE 7

scrapie sheep CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Transmissible Spongiform Encephalopathy Prion diseases

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SLIDE 8

CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Gerstmann-Sträussler-Schenker (GSS) syndrome

Symptoms: Dementia (loss of cognitive ability) Ataxia, Myoclonus (loss of muscle control, twitching) Duration: 1-15 years after symptoms, starts usually at 25-50 yrs Cause: familial, autosomal dominant inheritance

scrapie sheep

Source: Ridley, Baker, 1998, Fatal Protein, p. 77ff, 88
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SLIDE 9

CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

kuru humans Gerstmann-Sträussler-Schenker (GSS) syndrome

Symptoms: Dementia (loss of cognitive ability) Ataxia, Myoclonus (loss of muscle control, twitching) Duration: 1-15 years after symptoms, and then you die Cause: familial, autosomal dominant inheritance

GSS humans scrapie sheep

Source: Ridley, Baker, 1998, Fatal Protein, p. 77ff, 88
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SLIDE 10

CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Fatal Familial Insomnia (FFI)

Symptoms: Insomnia, Hallucinations, complete inability to sleep, weight loss, Dementia Duration: 7-15 months after symptoms Cause: familial, autosomal dominant inheritance

scrapie sheep

Source: Ridley, Baker, 1998, Fatal Protein, p. 87f; Soto, 2006, Prions, the new biology of proteins, p. 4
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SLIDE 11

CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Fatal Familial Insomnia (FFI)

Symptoms: Insomnia, Hallucinations, complete inability to sleep, weight loss, Dementia Duration: 7-15 months after symptoms, and then you die Cause: familial, autosomal dominant inheritance

scrapie sheep

Source: Ridley, Baker, 1998, Fatal Protein, p. 87f; Soto, 2006, Prions, the new biology of proteins, p. 4
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SLIDE 12

CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Kuru

Symptoms: Ataxia, then: Dementia Duration: 2-24 months, after incubation period 2-20 years Cause: eating brains

scrapie sheep

Source: Ridley, Baker, 1998, Fatal Protein, p. 40ff
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SLIDE 13

CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Kuru

”Within the highlander population the disease has been virtually eliminated since the cessation of the handling and eating of the brains of deceased relatives” – Claudio Soto, Prions, the new Biology of Proteins, p. 3

scrapie sheep

Source: Ridley, Baker, 1998, Fatal Protein, p. 40ff
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SLIDE 14

scrapie sheep CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Bovine Spongiform Encephalopathy (BSE)

Symptoms: nervousness, hyper-responsive to touch, tendency to kick abnormalities in walking ability, difficulty to maintain balance Duration: 1-2 months, after incubation period 4-5 years Cause: primary: probably cross-infection from sheep scrapie, allowed by changes in UK rendering practices secondary: feeding cattle with cattle meat bone meal

Source: Ridley, Baker, 1998, Fatal Protein, p. 153; Taylor D.M., Woodgate S.L., Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. Off. Int. Epiz. 2003, 22 (1) 297-310
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SLIDE 15
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SLIDE 16
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SLIDE 17

scrapie sheep CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Bovine Spongiform Encephalopathy (BSE)

Symptoms: nervousness, hyper-responsive to touch, tendency to kick abnormalities in walking ability, difficulty to maintain balance Duration: 1-2 months, and then they die Cause: primary: probably cross-infection from sheep scrapie, allowed by changes in UK rendering practices secondary: feeding cattle with cattle meat bone meal

Source: Ridley, Baker, 1998, Fatal Protein, p. 153; Taylor D.M., Woodgate S.L., 2003, Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. OIE 22(1): 297-310
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SLIDE 18

scrapie sheep CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Bovine Spongiform Encephalopathy (BSE)

Symptoms: nervousness, hyper-responsive to touch, tendency to kick abnormalities in walking ability, difficulty to maintain balance Duration: 1-2 months, and then they die, and then you die Cause: primary: probably cross-infection from sheep scrapie, allowed by changes in UK rendering practices secondary: feeding cattle with cattle meat bone meal

Source: Ridley, Baker, 1998, Fatal Protein, p. 153; Taylor D.M., Woodgate S.L., 2003, Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. OIE 22(1): 297-310
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SLIDE 19

scrapie sheep CWD deer BSE

cattle

FSE

cats

CJD

humans

FFI

humans

GSS humans kuru humans Transmissible Spongiform Encephalopathy Prion diseases

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SLIDE 20

Creutzfeldt-Jakob Disease

Did you ever... ...then... ...and... have parents? get surgery? eat beef? do nothing?

Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff
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SLIDE 21

Creutzfeldt-Jakob Disease

Did you ever... ...then... ...and... have parents? get surgery? eat beef? do nothing?

Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff

”...lifelong vegetarian who had no family history, never had surgery, had never worked on a farm, or in a butcher's shop, and who had never left Britain” – Fatal Protein, p. 91

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Creutzfeldt-Jakob Disease

Did you ever... ...then... ...and... have parents? get fCJD get surgery? get iCJD eat beef? get vCJD do nothing? get sCJD

Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff

”...lifelong vegetarian who had no family history, never had surgery, had never worked on a farm, or in a butcher's shop, and who had never left Britain” – Fatal Protein, p. 91

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SLIDE 23

Creutzfeldt-Jakob Disease

Did you ever... ...then... ...and... have parents? get fCJD die slowly get surgery? get iCJD die early eat beef? get vCJD die later do nothing? get sCJD die quickly

Source: Soto, 2006, Prions, the new biology of proteins, p. 2ff R I P
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SLIDE 24

… brains!

Observations:

  • Spongiform degeneration

diffuse or focally clustered small, round vacuoles

  • Neuronal apoptosis

cause of brain malfunction

  • Astrogliosis

increase in astrocytes due to neuron destruction

  • Amyloid deposition

plaques of PrPSc

Source: Soto, 2006, Prions, the new biology of proteins, p. 8 R I P
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Neuronal Apoptosis

Apoptosis

Caspase-3 activation Caspase-12 activation Caspase-12 ER Ca2+ ER stress

R I P Source: inspired by Soto, 2006, Prions, the new biology of proteins, fig. 7.2 p. 77
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Neuronal Apoptosis

Apoptosis

Caspase-3 activation Mitochontrial stress Death receptor Caspase-12 activation Caspase-12 ER Ca2+ ER stress

R I P Source: inspired by Soto, 2006, Prions, the new biology of proteins, fig. 7.2 p. 77
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SLIDE 27

Three Hypotheses

  • Virus

extremely slow acting virus infectious means bacteria or viruses But: too small, to resistant to UV and radiation

  • Virino

compact and highly resistant protein coat around a small informational molecule But: no evidence

  • Protein-only

proteinaceous infectious particle – prion infectious misfolded protein that replicates by misfolding other proteins

Source: Soto, 2006, Prions, the new biology of proteins, p. 13ff R I P
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SLIDE 28

Meet PrP – The Prion Protein

Source: The Protein Data Bank, ID: 1DX0; Lopez-Garcia, F., Zahn, R., Riek, R., Wuthrich, K.: NMR Structure
  • f the Bovine Prion Protein Proc.Nat.Acad.Sci.USA 97 pp. 8334 (2000); PrPSc image from http://www.biophys.uni-duesseldorf.de/research/prions/index.html

Bovine prion protein residues 23-230

PrPC

prion exhibiting β-sheet structure

PrPSc

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Meet PrP – The Prion Protein

PrPC PrPSc In short: PrPSc facilitates production of PrPSc from PrPC fibrilous PrPSc-structures block reverse conformational change strong bonding of β-sheets results in protease resistance

Source: Alberts et al., Molecular Biology of The Cell, 5th edition, p. 397
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Eradicating PrPSc

  • originally found as PrP27-30,

protease-resistent protein, with a weight of 27-30 kDa

  • pre-protease-treatment examination found PrP33-35
  • part of the problem behind the BSE epidemic:

incomplete inactivation and high resistance to inactivation

  • Autoclaving at 133°C, 3 bar for 20 minutes destroys prions

if high-risk tissues (brain, spinal cord) are reliably excluded

Source: Ridley, Baker, 1998, Fatal Protein, p. 106ff; Taylor D.M., Woodgate S.L., 2003, Rendering practices and inactivation of transmissible spongiform encephalopathy agents, Rev. Sci. Tech. OIE 22(1): 297-310 R I P
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Detecting PrPSc

  • Detecting PrPSc qualitatively is very difficult
  • established procedures work on DNA (PCR)

and RNA (RT-PCR), but not on proteins

  • no immunoresponse, no antibodies
  • detection in vivo only after onset of symptoms,
  • ie. after brain damage
  • high concentration in brain tissue,

low concentration in blood

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Protein Misfolding Cyclic Amplification

PrPC + PrPSc seed PrPSc amyloid

R I P Source: diagram inspired, but not copied, from Soto, 2006, Prions, the new biology of proteins, p. 116
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SLIDE 33

Protein Misfolding Cyclic Amplification

PrPC + PrPSc seed PrPSc amyloid Sonification

R I P Source: diagram inspired, but not copied, from Soto, 2006, Prions, the new biology of proteins, p. 116
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SLIDE 34

Protein Misfolding Cyclic Amplification Protein Misfolding Cyclic Amplification

PrPC + PrPSc seed PrPSc amyloid Catalysed by unknown protein X PMCA needs a secret ingredient:

Source: Soto, 2006, Prions, the new biology of proteins, p. 117 R I P
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SLIDE 35

Protein Misfolding Cyclic Amplification Protein Misfolding Cyclic Amplification

PrPC + PrPSc seed PrPSc amyloid Catalysed by unknown protein X PMCA needs a secret ingredient:

Brain homogenate

scientific euphemism for brain + blender

Source: Soto, 2006, Prions, the new biology of proteins, p. 117 R I P
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SLIDE 36

Curing Prion Diseases

7 ideas:

  • Reduce PrP expression
  • Block PrP – X interaction
  • Inhibit PrPC – PrPSc interaction
  • Prevent PrPC conversion
  • Reverse PrPSc conformation
  • Enhancing PrPSc clearance
  • Blocking PrPSc neurotoxicity
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Curing Prion Diseases

7 problems:

  • Reduce PrP expression
  • Block PrP – X interaction
  • Inhibit PrPC – PrPSc interaction
  • Prevent PrPC conversion
  • Reverse PrPSc conformation
  • Enhancing PrPSc clearance
  • Blocking PrPSc neurotoxicity
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SLIDE 38

Still want more?

Did we tell you the whole truth?

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SLIDE 39

Still want more?

Did we tell you the whole truth? No.

R I P
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SLIDE 40

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
R I P
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SLIDE 41

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
  • PrPSc occurs naturally in the brain
R I P Source: Yuan J., Xiao X., McGeehan J., Dong Z., Cali I., Fujioka H., Kong Q., Kneale G., Gambetti P., Zou W.-Q., 2006, Insoluble Aggregates and Protease-resistant Conformers of Prion Protein in Uninfected Human Brains, J. Biol. Chem. 2006 281: 34848-34858. First Published on September 20, 2006, doi:10.1074/jbc.M602238200
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SLIDE 42

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
  • PrPSc occurs naturally in the brain
  • There isn't one PrPSc – there are many
R I P
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SLIDE 43

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
  • PrPSc occurs naturally in the brain
  • There isn't one PrPSc – there are many
  • We can create new, incurable, fatal diseases
R I P Source: Barria M.A., Mukherjee A., Gonzalez-Romero D., Morales R., Soto C., 2009, De Novo Generation of Infectious Prions In Vitro Produces a New Disease Phenotype, PLoS Pathog 5(5): e1000421. doi:10.1371/journal.ppat.1000421
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SLIDE 44

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
  • PrPSc occurs naturally in the brain
  • There isn't one PrPSc – there are many
  • We can create new, incurable, fatal diseases
  • Different prion conformations are competing
R I P
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SLIDE 45

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
  • PrPSc occurs naturally in the brain
  • There isn't one PrPSc – there are many
  • We can create new, incurable, fatal diseases
  • Different prion conformations are competing
  • In a Darwinian sense – adaptation and selection
R I P Source: Li J., Browning S., Mahal S.P., Oelschlegel A.M., Weissmann C., 2010, Darwinian Evolution of Prions in Cell Culture, Science 327 (5967), 869. [DOI: 10.1126/science.1183218]
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SLIDE 46

Still want more?

Did we tell you the whole truth? No.

  • PrPC knockout mice are resistant
  • PrPSc occurs naturally in the brain
  • There isn't one PrPSc – there are many
  • We can create new, incurable, fatal diseases
  • Different prion conformations are competing
  • In a Darwinian sense – adaptation and selection
  • Where is your central dogma now?
R I P
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SLIDE 47

The End.

...and then you die

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