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The 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
PrPc
PrPsc
soluble
+
-
enzyme
digesting
+
-
polypeptide
chain
ɑ-helical
segment
ß-sheet
67
•PrPc
•PrPsc
• Mutant polypeptide might be less stable
and more likely to fold into the abnormal
PrPsc 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 disease
• Personwith AD exhibit memory loss,
confusion, and a loss of reasoning
ability.
67 2
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(Aß), which is originally
part of a larger protein called the amyloid
precursor protein(APP), which spans the
nerve cell membrane.
ß-
secretase,
ř-secretase,
Aß peptide
67 3
PS1 and PS2
Ab40 and Ab42
• Both of these peptides can exist in a
soluble form that consists
predominantly of a-helices, but Aß42
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。