Protein Misfolding
Can Have Deadly
Consequences
Yu Tiantian
Li Yihan
In April 1996 a paper was published in the
medical journal Lancet that generated
widespread alarm in the populations of
Europe.
 The paper described a study of 10
persons afflicted with Creutzfeldt-Jakob
disease (CJD), a rare, fatal disorder that
attacks the brain, causing a loss of motor
coordination and dementia.

CJD


Creutzfeldt–Jakob disease or CJD is a
degenerative neurological disorder (brain
disease) that is incurable and invariably
fatal.The disease is at times called a human
form of Mad Cow disease given the fact that
Bovine spongiform encephalopathy is the cause
of variant Creutzfeldt-Jakob disease in humans.
This means that the brain develops holes and
takes on a sponge-like texture.
Like numerous other diseases, CJD can
occur as an inherited disease that runs in
certain families.
 Unlike virtually every other inheritable
disease CJD can also be acquired.
 Until recently, persons who had acquired
CJD had been recipients of organs or
organ products that were donated by a
person with undiagnosed CJD.

???

A disease that runs in families can
invariably be traced to a faulty gene,
whereas diseases that are acquired from a
contaminated source can be traced to an
infectious agent.
 How
can the same disease be both
inherited and infectious?
Kuru



Gajdusek showed that these islanders were
contracting a fatal neurodegenerative disease—
which they called “kuru”—during a funeral ritual
in which they ate the brain tissue of a recently
deceased relative.
Autopsies of the brains of patients who had died
of kuru showed a distinct pathology, referred to
as spongiform encephalopathy, in which
certain brain regions were riddled with
microscopic holes (vacuolations), causing the
tissue to resemble a sponge.
It was soon shown that the brains of islanders
suffering from kuru were strikingly similar in
microscopic appearance to the brains of persons
afflicted with CJD.
Infection
Kuru
Daniel Carleton Gajdusek

Daniel Carleton Gajdusek
(1923–2008) was an
American physician and
medical researcher who was
the co-recipient (with Baruch
S. Blumberg) of the Nobel
Prize in Physiology or
Medicine in 1976 for work
on kuru, the first human
prion disease demonstrated
to be infectious.
Infection
In 1968, Gajdusek showed that when
extracts prepared from a biopsy of the
brain of a person who had died from CJD
were injected into a suitable lab animal,
that animal did indeed develop a
spongiform encephalopathy similar to
that of kuru or CJD.
 Clearly, the extracts contained an
infectious agent.

Stanley Ben Prusiner

Stanley Ben Prusiner
(1942- ) is an American
neurologist and biochemist.
Prusiner discovered
prions, He received the
Albert Lasker Award for
Basic Medical Research in
1994 and the Nobel Prize
in Physiology or Medicine
in 1997 for his prion
research.
Prion
A prion is an infectious agent
composed of protein in a misfolded
form. This is in contrast to all other known
infectious agents, which must contain
nucleic acids (either DNA, RNA, or both)
along with protein components.
 Unlike viruses, the prion that infectious
agent responsible for CJD lacked nucleic
acid and instead was composed solely of
protein.

PRPN


The prion protein was soon shown to be
encoded by a gene (called PRNP) within the
cell’s own chromosomes. The gene is
expressed within normal brain tissue and
encodes a protein designated PrPC (standing for
prion protein cellular) that resides at the surface
of nerve cells.
The precise function of PrPC remains a mystery.

A modified version of the protein(PrPSc)is present in
the brains of humans with CJD. Unlike the normal
PrPC, PrPSc accumulates within nerve cells, forming
aggregates that kill the cells.
PrPc Vs. PrPSc
PrPc
PrPSc
molecular
monomeric
fibrils
Soluble or not
soluble
insoluble
sensitivity
insensitive
sensitive
Stability of
protein
stable
unstable
Tertiary structure α-helical
About 45% βsheet
Pathogenicity
pathogenic
Not pathogenic

An abnormal prion molecule (PrPSc) can bind to
a normal protein molecule (PrPC) and cause the
normal protein to fold into the abnormal form.

This conversion can be shown to occur in the
test tube: addition of PrPSc to a preparation of
PrPC can convert the PrPC molecules into the
PrPSc conformation.
CJD’s acquire
Inherited
 Infection
 Surgical instruments


All this situation is started a chain reaction
in which normal protein molecules in the
cells are gradually converted to the
abnormal prion form.
Alzheimer’s disease
(AD)
Alzheimer’s disease
(AD)

10 percent of individuals who are at least
65 years of age

40 percent of individuals who are 80 years
or older
Alzheimer’s disease
(AD)
Clinical symptoms：
 memory loss
 confusion
 a loss of reasoning
 repeat language
 meaningless repetitive movements
Comparison of AD and CJD

Similarities:
 fatal
neurodegenerative diseases
 contain
fibrillar deposits of an insoluble
material
Comparison of AD and CJD

Differences:
 The
proteins that form the disease-causing
aggregates are unrelated.
 The parts of the brain that are affected are
distinct.
 The protein responsible for AD is not an
infectious agent.
Causes of AD
AD is caused by the production of a molecule,
called the amyloid β-peptide (Aβ)
 Aβ
is originally part of a larger protein called
the amyloid precursor protein (APP), which
spans the nerve cell membrane.
The Aβ peptide is released from the APP molecule
following cleavage by two specific enzymes,β-secretase
and γ-secretase.
The types of the Aβ peptide
The one species has a length of 40 amino
acids (designated as Aβ40).
 Another species is with two additional
hydrophobic residues (designated as Aβ42)


It is the misfolded Aβ42 version of the molecule
that has the greatest potential to cause damage
to the brain.

Overproduction of Aβ42 can be caused by
mutations in the APP gene or in genes
(PS1,PS2) that encode subunits of γ-secretase.
Normal
Alzheimer’s
Experiment on animal model

Animal model:
the genetically engineered mice
Basis of experiment
Injecting the animals with the very same
substance that causes the problem, the
aggregated Aβ42 peptide.
Preclinical test
Phase I clinical trial
Carried out on a small number of subjects
and designed to monitor the safety of the
procedure.
 Outcomes
No ill-effects from the injection of the
amyloid peptide

Preclinical test
Phase II clinical trial
A large group of subjects and designed to obtain
a measure of the effectiveness of the procedure.
 Outcomes
Discontinued because of the serious side effect.
However, 30 of the patients continued to be
tested from the study provided dramatic
evidence that the vaccine had had a major
impact on slowing disease progression.

Preclinical test
Phase III clinical trial
Employ large numbers of subjects and
compares the effectiveness of the new
treatment with standard approaches.
 Outcomes
No outcomes.

Other therapeutic strategies


Nonsteroidal anti-inflammatory medications
Cholestero-lowering medications called statins
Have a markedly reduced incidence of
Alzheimer’s disease.
Have already approved for human use and have
been taken by tens of millions of people.