Cellular Stress and Protein Misfolding During Aging - Protein Misfolding and Cellular Stress in Disease and Aging - page 110

Table 1
Representative protein misfolding diseases showing the proteins involved, the
cellular location in which they fold, and the basic molecular pathogenesis

Protein involved Location Pathogenic mode Disease

b-amyloid C/E Gain-of-function Alzheimer's disease

Crystallin C Gain-of-function Cataract

CFTR ER Loss-of-function Cystic Fibrosis

Prion ER Loss-of-function Creutzfeldt-Jakob disease or CJD

a-1-antitrypsin ER Loss-of-function a-1-antitrypsin deficiency

Transthyretin (TTR)/
Lysozyme

ER Gain-of-function Familial amyloidosis

SCAD variants M Loss-of-function Short-chain acyl-CoA dehydroge-

nase (SCAD) deficiency

LDL receptor ER Loss-of-function Familial hypercholesterolemia

C cytoplasm, E extracellular, ER endoplasmic reticulum, M mitochondria

Huntington's disease. Table 1 lists some of the known protein
misfolding or protein conformational diseases, the proteins
involved in such disorders, their cellular location, and the sug-
gested molecular pathogenesis.

3.4. Errors and
Damage in Proteins

Since, the error frequency of amino acid misincorporation is gen-
erally considered to be quite high ( 3 ) as compared with nucleotide
misincorporation (less than 10 −6 ), the role of protein error feed-
back in aging has been a widely discussed issue, and is the basis of
the so-called error catastrophe theory of aging ( 3, 39 ) . So far, no
direct estimates of protein error levels in any aging system have
been made, primarily due to the lack of appropriate methods to
determine spontaneous levels of errors in a normal situation.
However, several indirect estimates of the accuracy of translation
in cell-free extracts, using synthetic templates or natural mRNAs
have been made. Studies performed on various young and old
animal tissues such as chick brain, mouse liver, and rat brain, liver,
and kidney, and human cells undergoing aging in vitro did reveal
some age-related increase in protein errors ( 3, 39 ). Furthermore,
an induction and increase in protein errors has been shown to
accelerate aging in human cells and bacteria ( 1, 40 ). It will be
important to know if there is a direct link between increased pro-
tein errors and increased protein misfolding during aging.
A large number of post-translational modifications of proteins
have been described that determine the activity, stability, specific-
ity, transportability, and lifespan of a protein. Several of these
modifications are highly specific and regulated involving various