The Mitochondrial Chaperone Protein TRAP1 Mitigates alpha-Synuclein Toxicity

Overexpression or mutation of alpha-Synuclein is associated with
protein aggregation and interferes with a number of cellular
processes, including mitochondrial integrity and function. We used
a whole-genome screen in the fruit fly Drosophila melanogaster to
search for novel genetic modifiers of human A53T]
alpha-Synuclein-induced neurotoxicity. Decreased expression of the
mitochondrial chaperone protein tumor necrosis factor receptor
associated protein-1 (TRAP1) was found to enhance age-dependent
loss of fly head dopamine (DA) and DA neuron number resulting from
A53T] alpha-Synuclein expression. In addition, decreased TRAP1
expression in A53T] alpha-Synuclein-expressing flies resulted in
enhanced loss of climbing ability and sensitivity to oxidative
stress. Overexpression of human TRAP1 was able to rescue these
phenotypes. Similarly, human TRAP1 overexpression in rat primary
cortical neurons rescued A53T] alpha-Synuclein-induced sensitivity
to rotenone treatment. In human (non) neuronal cell lines, small
interfering RNA directed against TRAP1 enhanced A53T]
alpha-Synuclein-induced sensitivity to oxidative stress treatment.
A53T] alpha-Synuclein directly interfered with mitochondrial
function, as its expression reduced Complex I activity in HEK293
cells. These effects were blocked by TRAP1 overexpression.
Moreover, TRAP1 was able to prevent alteration in mitochondrial
morphology caused by A53T] alpha-Synuclein overexpression in human
SH-SY5Y cells. These results indicate that A53T] alpha-Synuclein
toxicity is intimately connected to mitochondrial dysfunction and
that toxicity reduction in fly and rat primary neurons and human
cell lines can be achieved using overexpression of the
mitochondrial chaperone TRAP1. Interestingly, TRAP1 has previously
been shown to be phosphorylated by the serine/threonine kinase
PINK1, thus providing a potential link of PINK1 via TRAP1 to
alpha-Synuclein.