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  • Florey Department of Neuroscience and Mental Health
  • Florey Department of Neuroscience and Mental Health - Research Publications
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    iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.

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    Author
    Arber, C; Angelova, PR; Wiethoff, S; Tsuchiya, Y; Mazzacuva, F; Preza, E; Bhatia, KP; Mills, K; Gout, I; Abramov, AY; ...
    Date
    2017
    Source Title
    PLoS One
    Publisher
    Public Library of Science (PLoS)
    University of Melbourne Author/s
    Duce, James
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Arber, C., Angelova, P. R., Wiethoff, S., Tsuchiya, Y., Mazzacuva, F., Preza, E., Bhatia, K. P., Mills, K., Gout, I., Abramov, A. Y., Hardy, J., Duce, J. A., Houlden, H. & Wray, S. (2017). iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.. PLoS One, 12 (9), pp.e0184104-. https://doi.org/10.1371/journal.pone.0184104.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257084
    DOI
    10.1371/journal.pone.0184104
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581181
    Abstract
    Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.

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