Cellular Stress and Protein Misfolding During Aging - Protein Misfolding and Cellular Stress in Disease and Aging - page 109

and more importantly by their impact on protein sequence.
However, generally mutations are classified based on their effect
on the primary structure, and as such have three main types -
point mutations, deletions, and insertions. Point mutations can
be further subdivided into: (i) silent mutations - which code for
similar amino acids; (ii) missense mutations - which code for dif-
ferent amino acids; and (iii) nonsense mutations - which code for
a stop codon and can result in a truncated gene product.
For large deletions and, in most cases, stop mutations, the
deleterious effect is obvious as the function of the affected poly-
peptide product is abolished. However, for missense mutations or
short in-frame insertions and deletions, the disease-causing nature
of the mutation is not directly evident ( 33 ). The Human Gene
Mutation Database contains, at present, close to 88,000 entries
on mutations in genetic diseases, of which approximately 49,000
entries are missense mutations ( 34 ). Missense mutations and
short in-frame deletions and insertions often impair the propen-
sity of the affected polypeptide to fold to the functional confor-
mation, and/or decrease the stability of the functional
conformation. Both effects lead to an increase in the proportion
of mutant polypeptide present in nonfunctional conformations
that are more susceptible to degradation or aggregation than the
functional conformation.
Thus, diseases arising from misfolded or non-functional
conformations were termed as conformational diseases ( 35 ),
referring to conditions in which aggregation due to aberrant
folding of a polypeptide appears to be the molecular pathological
mechanism, as for example in Alzheimer's disease (AD) and
Creutzfeldt-Jakob's disease. However, in a wider definition ( 36 ),
conformational diseases were linked to disturbances of the folding
process in general ( 37 ), thereby distinguishing two subgroups:
one covered by the appearance of aggregating proteins and a
second group of diseases in which impaired folding leads to rapid
degradation of the affected polypeptides (e.g., cystic fibrosis and
most forms of a-1-antitrypsin deficiency).
Over the years, a large number of human diseases have been
linked to conformational upheavals or misfolding. The involve-
ment of mutations in these diseases has also resulted in an alter-
nate classification of these diseases by their effect on function.
Inherited disorders like cystic fibrosis are due to amino acid
substitutions that exhibit a loss-of-function pathogenesis because
the aberrant protein is eliminated by the protein quality control
system in the ER ( 38 ). However, not all aberrant proteins can be
eliminated and the misfolded protein may accumulate and form
toxic oligomeric and/or aggregated inclusions. In this case, the
loss of function of a protein may be accompanied by a gain-of-
function pathogenesis, which in many cases determines the path-
ological and clinical features, examples being Parkinson's and