The neuropathology of mitochondrial disease: insights gained from the Ndufs4fky/fky mouse and Friedreich's ataxia induced pluripotent stem cell-derived neurons
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2014
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Melbourne Authors
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Paediatrics (RCH)
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PhD thesis
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© 2014 Dr. Matthew John Bird
Abstract
Mitochondrial dysfunction, in particular disorders of oxidative phosphorylation (OXPHOS), causes a range of early-onset neurological conditions. The mechanisms though of the neuronal damage are poorly understood, as accessing biologically relevant neurological tissue has traditionally been difficult.
To better understand the mechanisms of neurodegeneration in patients with mitochondrial disease, I have assessed mitochondrial function in several neurologically relevant primary cell lines from a mouse that mimics aspects of the mitochondrial disease, Leigh (like) syndrome (LS), the Ndufs4fky/fky mouse. The Ndufs4fky/fky mouse carries a knockout of the NDUFS4 protein subunit, one of 44 subunits that comprise the mammalian mitochondrial respiratory chain complex I (CI).
I find that CI structure and function is equally disrupted in primary Ndufs4fky/fky neurons, astrocytes and mouse embryonic fibroblasts (MEFs) compared to +/+ cells. However, the affect of this disruption on the OXPHOS system, and mitochondrial function more generally, varied between the three different primary cell types examined. This in turn has provided insight to the disease specificity of the LS, and why neurological function is particularly susceptible in mitochondrial disease.
In addition to studies in the Ndufs4fky/fky mouse, I also characterised mitochondrial function in Friedreich’s ataxia (FA) induced pluripotent stem cell (iPSC)-derived neurospheres to better understand the neuropathology of FA. These FA iPSCs were generated from patients harbouring GAA triplet repeat expansions in the first intron of the frataxin gene (FXN) of greater then 500 repeats, well above the disease causing threshold of 50 repeats. I find that despite FXN protein expression being significantly reduced (≈ 35% of controls), mitochondrial function was normal. Considering no defect in mitochondrial function was revealed in these studies, it is possible that FXN expression in these cells is sufficient to perform synthesis of iron-sulfur clusters. Accordingly, FXN protein expression may need to be further reduced to disrupt mitochondrial activity. Alternatively, it may be indicative of mitochondrial function in the neuronal cell types of FA patients, whereby alternative disease mechanisms are at play.
In summary, these studies are significant for establishing LS and FA disease model systems, and highlight the importance of studying relevant cell types to disease.
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mitochondrial disease, neuropathology, Leighs syndrome, Friedreich's ataxia, mouse models, induced pluripotent stem cells