Protein Misfolding Can Have Deadly Consequences

Yu TiantianLi Yihan

In April 1996 a paper was published in the medical journal LancetLancet 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 degen

erative 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.

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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 How can the same disease be both inherited and infectious?inherited and infectious?

Kuru Gajdusek showed that these islanders were cont

racting 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.

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.

Infection

Stanley Ben Prusiner Stanley Ben Prusiner (19

42- ) 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 compose

d 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% β-sheet

Pathogenicity Not pathogenic 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 ADAD is caused by the production of a molecule, calle

d 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

Injecting the animals with the very same substance that causes the problem, the aggregated Aβ42 peptide.

Basis of experiment

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.