Roșianu, Flavia; (2022) The roles of NDR1/2 kinases in neuronal membrane trafficking and protein homeostasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

NDR1 and NDR2 (NDR1/2) are conserved serine/threonine kinases implicated in cell cycle regulation, cell polarisation, neuronal development and autophagy. The roles of NDR1/2 in mammalian neurons in vivo have not been explored. Using constitutive Ndr1 and/or neuron-specific Ndr2 knockout mouse models, we show that only loss of both Ndr1 and Ndr2 causes neurodegeneration with progressive accumulation of p62 and ubiquitinated proteins. Neurons in Ndr1/2 knockout mice have reductions in autophagosome numbers, but autolysosomes still form, indicating that autophagosome formation is impaired. Several endosomal compartments are altered, with increases in vesicles positive for Rab5, VPS35 and TfR, while the transmembrane ATG9A protein shows reduced axonal trafficking and accumulation at synaptic sites. Phosphoproteomics identified the endocytosis protein Raph1/ Lpd as a novel NDR1/2 substrate. Endocytosis is downregulated in neurons depleted of NDR1/2 or Raph1 and results in higher levels of ATG9A and TfR at the surface of the cell. Alterations in ATG9A trafficking and localisation are known to negatively impact autophagy, so the ATG9A phenotype likely contributes to reduced autophagy. We conclude that NDR1/2 are required for membrane and ATG9A trafficking, as well as efficient autophagy, and loss of NDR1/2 kinases leads to neurodegeneration in vivo.

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