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April 17-18, 2019 | Frankfurt, Germany
Parkinson’s, Huntington’s & Movement Disorders
International Conference on
Journal of Brain and Neurology | Volume 3
Alpha synuclein impairs structural and functional integrity of mitochondria in human
dopaminergic neurons
Goutham Kumar Ganjam
University of Marburg, Germany
Alpha synuclein (aSyn) is strongly linked to
Parkinson’s disease but the molecular targets
for its toxicity remains elusive. Rapidly evolving
concepts of PD pathology suggest that variants of
aSyn accumulate within mitochondria leading to
neuronal demise. Nevertheless, the role of aSyn in
mitochondrial physiology is poorly defined. We aim
toinvestigatethedeleteriouseffectsofmitochondrial
localization of aSyn in human dopaminergic LUHMES
cells. Therefore, we have generated neuron specific,
adeno associated virus type 2 (AAV2) expressing
cytosolic as well as mitochondrial targeting aSyn,
and EGFP expressing viruses for respective controls.
Overexpression of either form of aSyn severely
disrupted dendritic network, electrical activity and
induced dopaminergic cell death. Both cytosolic
and mitochondrial aSyn induced mitochondrial
ROS formation, loss of ATP production and
membrane depolarization. Real-time analysis
of mitochondrial bioenergetics using Seahorse
Bioscience system following AAV infection elicited
a complete damage to mitochondrial respiration
capacity in dopaminergic neurons. Transmission
electron microscopy illustrated a number of
deformed cristae in cytosolic form and a complete
loss of cristae structure and massively swollen
mitochondria in mitochondrial targeted aSyn in
expressing cells. Furthermore, we could show for
the first time that inhibition of caspases by QVD
significantly ameliorated aSyn-induced cell death
and improved mitochondrial function in human
dopaminergic neurons. Overall, our findings show
that cytosolic as well as mitochondrial targeted
expression of aSyn is detrimental to dopaminergic
neurons and inhibition of caspases amended
this aSyn toxicity. Thus, caspase inhibitors may
provide therapeutic potential to prevent neuronal
degeneration in synucleinopathies, including PD.
Speaker Biography
Goutham Kumar Ganjam is a Principal Investigator in University of
Marburg, Germany. He is an expert in mitochondrial bioenergetics,
neurodegeneration, inflammation, Parkinson's disease, mentoring, design,
plan, execute, training graduates, etc.
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