MISFOLDING PROTEIN

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???

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• ???
• ???

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MISFOLDING PROTEIN DISEASE

• SUMMARY
• Prion structure and function
• Prion ????? PrPC?PrPSC?Disease
• Misfolding protein ???
• Disease Kuru,CJD,Parkinson,AD
• ?????

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Prion structure and function
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Prion ?????
Prion?????????,??????,?glycophosphatidyl(GPI)?????
?? PrPC ??????a-helix ,?PrPsc??ß-sheet ????????
??PrPC ?? PrPsc
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PrPc PrPsc
?? ?????????? ????????
???K ????,????,???? ????,??N?67?a.a. residue,??PrP27-30,PrPsc? PrP27-30?????
???? ???? ???
??? ? ?
???? ? 42 ß3 ? 38 ß43
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Prion ?????
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• PrPC???PrPSC
• ????PrPSC???????
• ???PrPSC????????????PrPC???PrPSC

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PrPC PrPSC
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???

• PrPc???????PrPsc,???????PrPsc???refolding?PrPsc,
  ??heterodimer??homodimer,??????????PrPc??

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???
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???

• ????????????PrPsc??,?????PrPsc????????oligomer?,??
  ??????????,???????,??????????PrPsc??????PrPc????Pr
  Psc,????????(amyloid)?

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???
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PrPsc ?? PrPc

• ????,PRPSC???????,??????PRPC????,???????????????PR
  PSC???,??????????PROTEIN?

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DISEASE

• PrPsc??????,??????????PrPsc????????,?????????,????
  ????,????????????,???????????

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Misfolding protein ???
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????????? misfolded protein?
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• ????????chaperones ? heat shock
  proteins???????????????(denaturing)???????????????
  ???????????
• Chaperone?????
• 1.???????,???????????????????????
• 2.????????(refold)????
• Chaperone??????????????????????

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?????????chaperones??chaperones???
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Chaperones??

• ?????????????????????
• chaperones???????????
• ??????
• chaperones????????????????
• chaperones???????????????????

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(No Transcript)
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• ????????????,??????????prion(PrPsc)-gt????-gt??
  ?PrPc????????PrPc??,?????(GroE1)?????????

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Disease
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????

• ?????--????(Creutzfeldt-Jakob disease),????????(C
  JD)??1920?????????,??????????,??????????0.51????

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???????

• ???????????,??????????,???????(spongiform
  encephalopathy,SE)?
• ??????????????????,??????????????????,????????????
  (transmissible spongiform encephalopathy,TSE)?
• ??????????,???????????????PrPSC(scrapie Prion
  Protein),?????????????PrPC (Cellular Prion
  Protein)???PrPSC?????????????????,???????????
• ??TSE??????????(Prion disease),??Prion????????(pro
  teinaceous infectious particles)??????TSE?????????
  ??

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????
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??

• ???? ???????
• ???? ????????????,???????????????(???),?????????
  ??????????????
• ?? ???????????????????????,?????????????????????
  ?????
• ?????????????
• ??????????,???????????,?????????????????

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????

• ???????????
• (1) ???
• (2) ???
• (3) ???
• (4)???????(new variant CJD, nv-CJD)

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???

• ?????????????
• ????????????????????????????????,??????????45?????
  ????
• ???????????????

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Distribution of infectivity in the human body
Infectivity category Tissues, secretions, and excretions
High infectivity Brain, spinal cord, eye
Low infectivity CSF, kidney, liver, lung, lymph node/spleen, placenta
No detectable infectivity Adipose tissue, adrenal gland, gingival tissue, heart muscle, intestine, peripheral nerve, prostate, skeletal muscle, testis, thyroid, tears, nasal mucous, saliva, sweat, serous exudate, milk, semen, urine, feces, blood
Data based on primates inoculated with CJD
tissues and naturally occurring animal TSEs
(WHO, 2000)
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???????

• ??,???????????????????????????????????????????????
  ????,??????????

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???
CJD
??
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???
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??

• ???,??????????????????,???????????.
• TSE??????,??????-BSE

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??

• ?????????????,????????????,????,??????????????,???
  ???????????

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KURU
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??

• ???(Kuru)???1950???????????,??????????????????????
  ?????????,?????????

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• ???????????????????????,?????????????????,?????

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??

• ??????????,????????????,??????????????,?????50????
  ??

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?????
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?????

• ????????????????,????????????????????????
• ?????????????,??????????,???DNA?RNA????,??????????
  
• ??????????????,???????????
• ?????????(???)?????????,?????????????????

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Histological features of TSE
Scrapie
kuru
vCJD
CJD
BSE
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Degenerative diseases
Huntingtons disease (caudate nucleus and frontal
cortex)

• Parkinson Disease ????
• Huntingtons Disease ?????
• Amyotrophic Lateral Sclerosis (ALS) ????????
• Alzheimer Disease (AD) ?????

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Alzheimer disease ?????

• ?????(Alzheimers disease,??AD)???????,???????????
  ??
• ???????,?????????????????

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Alzheimer disease ?????

• ??
• ?????????
• ???????
• ???????(????????????)??????????,?????????

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(No Transcript)
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Alzheimer disease
???
??
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• ???
• ????????(Familial AD FAD)?????????????????30?60?
  ???
• ?????????(Senile dementia with Alzheimer's type
  SDAT)???????????????????(60???)???

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• ??
• ???????????????(???),?????????????????
• ???????????????????????????????????AD?????????Pre
  senilin 1, Presenilin 2, Amyloid Precursor
  Protein
• ???AD(LOAD)??????????the epsilon 4 allele of the
  APOE gene???????50????
• ???????????????????????????????????ß???????????

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(No Transcript)
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Parkinson disease(????)

• ??
• ????????????????????
• ?????????,??????????(basal ganglia)????(substantia
  l nigra)???????,????????????????(Dopamine)????????
  ??
• ?????????????????????????????????

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• ??
• ?????(resting tremor)
• ??????????????????????????????????
• ??(rigidity)
• ??????????,???????????????
• ????(akinesia)?????(bradykinesias)
• ????????,???????
• ????????(postural instability)
• ?????????,?????????????
• ?????

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Parkinson Disease Gross
Depigmentation of the substantia nigra in PD
(left). Normal sustantia nigra (right)
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????

• ????????

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??????????(periodic sharp wave pattern)
70??????
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?????????????

• ??????????????

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?????????????

• ??????????14-3-3?????(95?????????)
• ????????????????
• ???????????14-3-3?????

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?????????????

• ??
• ???????
• ??????
• ???????
• ??????
• ??

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?????????????

• ??????????????14-3-3????????????
• ????????????cjd???????????

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?????

• ???

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????

• ????????

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????????

• ??????
• ???(myoclonus)
• ???????????(visual or cerebellar ataxia)
• ????/?????????(pyramidal/extrapyramidal
  dysfunction)
• ???????(akinetic mutism)

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??????(new variant cjd)???

• ????nv-cjd?????(?????????)

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?????

• ????(the pulvinar nuclei of the thalamus)
• ?????????

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????????

• Nv-cjd??????(???,?,??????)????
• ??????????????
• ???????

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????14-3-3

• ?????????cjd????????
• ????nv-cjd???????????????
• ?PRION??