The Human PerspectiveThe Human Perspective

----protein folding can have deadly consequences

• Creutzfeld-Jakob disease (CJD)

• Alzheimer’s disease (AD)

Creutzfeld-Jakob disease

• CJD, a rare, fatal disorder that attacks the brain, causing a loss of motor coordination and dementia.

• CJD can occur as an inherited disease, however, it can also be acquired.

• By the end of 2003, more than 125 cases of CJD had been traced to contaminated European beef, and efforts are still underway to determine the scope of the epidemic.

or

How can the same disease be both inherited and infectious?

• In the 1960s on a strange malady that once afflicted the native population of Papua, New Guinea.

• Be showed that these islanders were contracting a fatal neurodegenerative disease(神经组织退化） .

• Spongiform encephalopathy(海绵状脑病）• Kuru(新几内亚震癫病）

Did the brain of a person suffering from CJD, which was known to be an inherited disease, contain an infectious agent?

1968 Gajdusek

normal laboratory animal’ brain

+Brain of a died from CJD

person

Develop a spongiform encephalopathy similar to

CJD

1982 Stanley and Prusiner

• Unlike viruses, the agent responsible for CJD lack nucleic acid and instead was composed solely of protein---prion.

• The prion protein was shown to be encodes by a gene( called PRNP) within the cell’s own chromosomes.

• PrPc

• PrPsc 　　 PrPPrPcc PrPPrPscsc

solublesoluble ++ --

enzyme enzyme digestingdigesting ++ --

polypeptidpolypeptide chaine chain

ɑ-helical ɑ-helical segmentsegment ß-sheetß-sheet

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•PrPc •PrPsc

• Mutant polypeptide might be less stable and more likely to fold into the abnormal PrPs

c conformation, which can bind to a normal protein molecule(PrPc) and cat as a template that causes the normal protein to refold into the abnormal form.

Alzheimer’s diseaseAlzheimer’s disease • Personwith AD exhibit memory loss, co

nfusion, and a loss of reasoning ability.

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Like CJD, the brain of a person with Alzheimer’s disease contains fibrillar deposits of an insoluble material referred to as amyloid( 淀粉体） .

• Alzheimer’s disease is caused by the production of a molecule, called the amyloid-b-peptide(Aßß), which is originally part of a larger protein called the amyloid precursor protein(APP), which spans the nerve cell membrane.

ßß-secretase, ř-secretase, Aßß peptide

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PS1 and PS2

Ab40 and Ab42Ab40 and Ab42

• Both of these peptides can exist in a soluble form that consists predominantly of a-helices, but Aßß42 has a tendency to spontaneously refold into a very different conformation that contains considerable ß-pleated sheet. It tends to self-associate to form small complexes as well as large aggregates that are visible as fibrils in the electron microscope.

一个突变的朊病毒可以导致许多单个的蛋白彼此连接成串，就象一组人手拉手一样。其他的导致疾病的类朊病毒的蛋白都以二聚体成对出现。研究者推论这些成对的蛋白形成三维结构域交换状态，朊病毒可能也被诱导形成凝聚体。