|Ph.D Student||Hakim Ketty|
|Subject||The Role of Neuron-Glia Interactions in Neurodegeneration|
|Department||Department of Medicine||Supervisor||Dr. Estee Kurant|
|Full Thesis text|
Elimination of unnecessary neurons through apoptosis and subsequent phagocytosis is crucial for normal development of the CNS. Glial cells are the main phagocytes in the developing CNS and play a critical role in CNS sculpting by efficiently removing apoptotic neurons. However, the role of glial phagocytosis in the adult mature CNS, specifically its impact on neurodegeneration remains unclear.
In many neurodegenerative disorders, neuronal cell loss is accompanied by upregulated glial activity including phagocytosis. Vertebrate microglia, which are highly phagocytic, accumulate in the lesions of a variety of neurodegenerative disorders, and are thought to play both toxic and protective roles for neuronal survival. Moreover, activated microglia are able to phagocytose PS-exposing live neurons through a process called phagoptosis. However, whether glial phagocytosis per se may lead to reduction in neuronal number in vivo remains unclear.
Drosophila has no inflammation and adaptive immunity; therefore, it serves as a powerful model to study the role of glial phagocytosis in neurodegeneration independently of inflammation. Our and others’ previous studies have demonstrated that Drosophila glia are functionally and molecularly highly similar to their vertebrate counterparts. In phagocytosis, two transmembrane receptors SIMU and Draper have been shown to be required for glial elimination of apoptotic neurons during embryogenesis, while Draper is also involved in glial phagocytosis of injured axons in the adult brain.
In this work we aimed studying glia-neuron interactions in the adult brain focusing specifically on the effect of elevated glial phagocytosis on neuronal loss. Here we demonstrate that providing glia with increased levels of the glial phagocytic receptors SIMU or Draper leads to neuronal cell loss in the adult fly brain, accompanied by motor dysfunction and shorter life span of affected flies. Importantly, we revealed that this reduction in neuronal number is not a result of neuronal apoptosis, while SIMU protein domains that are obligatory for its phagocytic ability are essential for the neuronal loss. These data suggest phagoptosis as a possible mechanism of neuronal loss. Moreover, our results of masking PS with the bridging molecule MFGE-8 in adult glia exhibit significant rescue of climbing ability and survival rate of transgenic flies, strongly proposing that neuronal loss is PS-mediated. Altogether, this work provides experimental evidence for considering excess glial phagocytosis as a novel mechanism leading to neuronal loss in the adult brain.