What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 66

functioning neurons nearby ( 40 ). Another transgenic model
reported to accumulate mtDNA deletions and point mutations
by mutating the catalytic proofreading subunit of polymerase
gamma (polg) reported high mutations in the brain with coincid-
ing respiratory defects ( 41 ). However, two other independent
groups with a systematic and neuronal-specific mutant polg model
did not report neurodegeneration in the brain ( 42, 43 ). New
reported evidence indicates that previously reported deletions
from this model may really be replication intermediates due to
breakage at the origins of the heavy and light strand ( 44 ).

3.2. Future Directions
of Understanding
mtDNA Mutations

Severity and time of induction for these alterations in the mtDNA
are limiting factors in the current in vivo models in teasing out this
relationship between age-related neurodegeneration and the state
of mitochondrial genome. The accumulation of mtDNA muta-
tions or depletion levels cannot be controlled in these models
allowing them to accrue at folds higher than reported in postmor-
tem studies. This leaves us with the question of whether the physi-
ological levels of mtDNA mutations seen during natural aging
contributed to functional impairment. The induction of a defect
during development or in a mature organism also matters and can
change the possible phenotypic outcomes observed. With the
same mtDNA mutation load in the heart, the polg mouse accumu-
lates mutations beginning at 7 days postconception and the car-
diac-specific version of this mouse with mutations generated after
birth, show distinctly different cardiac phenotypes (reviewed in
( 45 )). Finally, most models manipulate genes with products that
control mitochondrial genome replication or repair (reviewed in
( 46 )). These genetic manipulations leave the mitochondrial
genome in a state of defenselessness exacerbating deficits that
would normally be repaired or compensated for, even in postmi-
totic neurons. Better models are needed to better define the role
of mtDNA and its ability to cause neurodegenerative events.
New models are being developed to study mtDNA deletions in
vivo and in culture specifically to study the mutations impact on neu-
rons. Fukui and Moraes created a mouse model that can inducibly
express a mitochondria-targeted restriction endonuclease ( Pst I). They
showed that expression of mito-Pst1 leads to the formation of large-
scale deletions ( 30 ). Another new exciting model has created neurons
derived from embryonic stem cell (ES) cybrids harboring mtDNA
point mutations. These models have already shown how point muta-
tions in complexes I and IV affect electrophysiological properties and
neurodegeneration in a neuronal cell phenotype ( 47 , 48 ).
In the future, these models may better reflect normal aging
and neurodegenerative processes. With the biggest risk factor for
neurodegenerative diseases being aging, accumulation of mtDNA
mutations in postmitotic cells could have a major impact on
senescence (reviewed in ( 49 )).