Sarajärvi, Verna Alina; (2020) Investigating cellular pathomechanisms of Charcot-Marie-Tooth disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies with over 90 causative genes identified to date. The mutations affect proteins with wide ranging cellular functions, including cytoskeletal structure, mitochondrial function, vesicle trafficking, as well as the cellular stress response. Despite the identification of several CMT-causing mutations, the underlying disease pathomechanisms remain unclear and there are currently no treatments. It is possible that common pathomechanisms may be involved in different forms of CMT, or conversely, there may be great specificity in the cellular changes caused by different mutations. The goal of this Thesis was to identify unique and common pathomechanisms between different CMT-causing mutations, using patient-derived skin fibroblasts and primary neuronal cultures as models of CMT. Basic cellular functions and morphology were investigated, with a particular focus on mitochondrial abnormalities and axonal transport. Patient fibroblasts with the following mutations were studied: i) CMT-causing mutations in mitochondrial genes – MFN2 and MT-ATP6; ii) optic atrophy-causing OPA1 mutation; iii) CMT-causing mutations in non-mitochondrial genes expressed in fibroblasts – HSPB1 and FIG4; iv) CMT-causing mutations in non-mitochondrial genes not expressed in fibroblasts – SH3TC2 and NEFL. In addition, a new in vitro model of CMT was developed, in which mouse primary motor and sensory neurons were transduced with 3rd generation lentiviruses to express CMT-causing mutations in MFN2, HSPB1 and NEFL. Alterations in mitochondrial membrane potential and morphology, as well as cellular calcium handling, were observed in fibroblasts and primary neurons expressing CMT-causing mutations linked to mitochondrial function. Surprisingly, similar functional and morphological mitochondrial abnormalities were also present in some cells expressing non-mitochondrial mutations. The MFN2 mutation also caused deficits in axonal transport of mitochondria. The extent of mitochondrial dysfunction varied between different mutations but was not limited to mutations in genes linked to mitochondrial function. Thus, mitochondrial dysfunction may be a common pathomechanism across different forms of CMT, and may therefore represent a therapeutic target applicable to a wide range of CMT subtypes.

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