Norkett, R; (2016) Contribution of the schizophrenia associated protein DISC1 to Mitochondrial Dynamics and Dendritic Development. Doctoral thesis , UCL (University College London).

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Abstract

Correct neuronal function is an energy costly process, highly dependent upon the ATP production and calcium buffering capabilities of mitochondria. Further, it is crucial that these organelles are correctly distributed throughout the neuron, matching local energy demand. To achieve this, mitochondrial fusion and transport dynamics must be precisely regulated. Trafficking is dependent upon microtubule based transport of these organelles, mediated by kinesin motors, TRAK adaptors and the mitochondrial anchor, Miro. Mitofusins orchestrate mitochondrial fusion at the outer membrane. Disrupted in schizophrenia 1 (DISC1) – a major candidate susceptibility factor for psychiatric disease – also plays a role in mitochondrial transport. However, the mechanisms of this regulation, and subsequent roles in neuronal development, are poorly understood. In this study, the interactions between DISC1 and mitochondrial trafficking proteins Miro and TRAKs are investigated. DISC1 is shown to couple to the mitochondrial transport and fusion machinery in brain. Live cell imaging demonstrates the importance of these interactions for normal mitochondrial transport. A schizophrenia associated mutation in DISC1 – the DISC1-Boymaw fusion protein – is shown to disrupt these transport dynamics and similarly impair mitochondrial fusion. Further, this mutation alters contact area between the endoplasmic reticulum and the mitochondria. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro/TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Finally, mitochondrial dynamics in human neurons, differentiated from induced pluripotent stem cells, are explored. This innovative system is used to investigate impact of pathogenic mutations associated with schizophrenia and Alzheimer’s disease upon mitochondrial dynamics. This work highlights DISC1 as an important regulator of mitochondrial dynamics in neurons to mediate transport, fusion and cross-talk of these organelles. Moreover, pathological DISC1 isoforms disrupt this critical function, leading to abnormal neuronal development. These findings implicate regulation of mitochondrial dynamics in aetiology of psychiatric disease.

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