What Role Does Mitochondrial Stress Play in Neurodegenerative Diseases? - Protein Misfolding and Cellular Stress in Disease and Aging - page 69

5. Protein
Aggregations
Associated with
Mitochondrial

In most neurodegenerative diseases, two events appear to coincide:
a region-specific degeneration of neuronal processes and a
misfolding/aggregation of abnormal proteins ( 66 ). The com-
position and identity of these mutant proteins differ depending
on the type of neurodegenerative disease; however, despite their
differences, at some stage of their aggregation, they all seem to
negatively impact on neuronal health. Some of the most com-
mon examples of these aggregations found in neurodegenera-
tive diseases include: Ab and hyperphosphorylated tau in
Alzheimer's disease, a-synuclein in Parkinson's disease, and
polyglutamine (CAG) repeats on protein in Huntington's dis-
ease ( 67 ). This correlative relationship between different forms
of protein aggregates and the rate of neurodegeneration is not
under debate; however, the causal relationship is still question-
able. Evidence for abnormal protein aggregations causing a
molecular cascade of deteriorating events has been shown, and
it is the increased proper clearance of intermediate oligomers (as
opposed to endpoint plaques or building monomers), that
improves symptoms of neurodegeneration ( 66, 68, 69 ). These
aggregated or mutant proteins in these pathologies have been
shown to affect mitochondria, leading to dysfunction as an addi-
tional source of organelle stress.

Ab has been found to interact with mitochondria and other pro-
teins thus leading to neuronal dysfunctions. Cyclophilin D, a sus-
pected mitochondrial permeability transition pore protein, has an
antagonistic association with Ab leading to decreases in calcium
buffering capacity, respiration, complex IV activity, and subse-
quently causes dysfunction at the synaptic and neuronal level
( 70 ). Mice overexpressing Amyloid Precursor Protein (APP)
show abnormal increases in Ab that cause decreases in complex
IV activity, ATP synthesis, and loss of membrane potential ( 71 ).
Ab interacting with Ab alcohol dehydrogenase (ABAD) also has
been shown to cause mitochondrial dysfunction, increased ROS,
and increased cell death ( 72 ).
There is also evidence of a mitochondria/aggregate interac-
tion in Parkinson's disease (PD). The accumulations of overex-
pressed a-synuclein protein specifically inhibits Complex I activity
in PD ( 73 ). Aged yeast models of PD that overexpress wild-type
and mutant A52T a-synuclein demonstrate that functional mito-
chondria with OXPHOS capacity are required and necessary for
this protein's toxicity ( 74 ). Fluorescence resonance energy trans-
fer (FRET) and biochemical fractionation gradient assays further
confirmed a a-synuclein protein interaction with native brain

5.1. Common
Aggregates and
Mitochondrial
Associations