Biology Reference
In-Depth Information
leading to imbalance in damage and repair capacity.
166-169
This is consistent
with accumulation of oxidative genome damage in the neurons for the majority
of such diseases including Alzheimer's disease (AD), Parkinson's disease (PD),
Huntington' disease, amyotrophic lateral sclerosis (ALS), and various ataxias.
Mutations or altered expression of BER (e.g., OGG1, XRCC1
170-172
) and
SSBR (e.g., TDP1, aprataxin, PNKP
39,43,173,174
) proteins has been observed
in humans predisposed to various hereditary neurodegenerative diseases.
Association between the XRCC1 Arg399Gln polymorphism and ALS risk was
reported.
175
A common Ser326Cys polymorphism in OGG1 with reduced
enzyme activity and increased risk of cancer was shown to be weakly associated
with HD and ALS,
176
but not with AD or PD.
171,177,178
Asp148Glu polymor-
phism in APE1 with lower repair activity, was linked to increased ALS risk.
179
Further, defects in end-processing proteins aprataxin and TDP1 have been
shown to be associated with ataxia with oculomotor apraxia1 and spinocerebel-
lar ataxia with axonal neuropathy, respectively.
173,180,181
A recent study linked
mutations in PNKP to autosomal-recessive disease characterized by severe
neurological abnormalities including microcephaly, early-onset
intractable
seizures, and developmental delay (denoted MCSZ
174
).
Decreased repair capacity for oxidative genome damage was also observed
in brain cell extracts in sporadic neurodegenerative diseases constituting
more than 80% of most disease incidences, whose causes are not known.
Weissman
et al.
169
showed that the significant BER deficiencies in the
brains of AD patients are due to limited DNA base damage processing by
DGs and reduced repair synthesis by Pol
b
. We recently showed that transi-
tion metals iron (Fe) and copper (Cu) that invariably accumulate in neurons
in these diseases significantly inhibit the activity of NEIL1 and NEIL2 at
physiological levels in both neuronal cells and
in vitro
.
182,183
These metals
affect both base excision and AP lyase activities of NEILs and inhibit
NEIL1's interaction with downstream repair proteins including Pol
b
, and
FEN-1, further inhibiting the overall repair. Inhibition of NEILs by Cu
involved oxidation of cysteines as well as structural changes via direct bind-
ing. The lack of OGG1 inhibition under similar conditions suggests binding
specificity of the NEILs and excludes metal ions' direct binding to DNA.
These results showed for the first time that the Fe/Cu overload associated
with neurodegenerative diseases could be a ''double whammy'' by increasing
oxidative genome damage load and, at the same time, inhibiting its repair.
Many other BER/SSBR proteins are also inhibited by transition metals.
Whiteside
et al.
showed that Cd and Cu inhibit both phosphatase and kinase
activities of PNKP with human cell extracts and recombinant protein.
184
Furthermore, elevated Fe levels cause reduction in FEN-1 and LigIII activ-
ities because of the interference of repair protein binding to their DNA
substrates.
185
