Axonal transport of autophagosomes in models of neurodegeneration in vitro and in vivo
von Xiaoyue Luo
Datum der mündl. Prüfung:2023-11-30
Erschienen:2023-12-14
Betreuer:Prof. Dr. Thomas Meyer
Gutachter:PD Dr. Jan C. Koch
Gutachter:PD Dr. Christian van Oterendorp
Dateien
Name:Luo Xiaoyue thesis.pdf
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Zusammenfassung
Englisch
Axonal degeneration is a prevalent hallmark of normal aging, trauma, and neurodegenerative CNS diseases. As an early event, it usually occurs prior to neuronal cell death, which has potential therapeutic implications. Importantly, autophagy, as a profoundly conserved metabolism of lysosomal degradation, is crucial for neuronal and axonal homeostasis. Notably, growing evidence suggests that autophagy may exert a dual function in axonal degeneration. The protective effect is mainly associated with the elimination of dysfunctional organelles and aggregated proteins, while excessive activation of autophagy is thought to promote neuronal loss. However, the precise function of autophagy in neurodegeneration still remains elusive, although changes in autophagic flux can be indirectly reflected by diverse monitoring analyses of autophagy-related molecules, including autophagic substrates. Therefore, advances in the field of live imaging, especially in animal models, enable us to closely monitor this process and develop a deeper comprehension of autophagy mechanisms. Based on a previous study in our lab indicating that autophagy was closely linked to axonal degeneration, the present research further explored the dynamic alterations of autophagy in several axonal degeneration models and tried to identify the potential molecular mechanisms. We found the retrograde transport capacity of autophagosomes is significantly diminished in multiple models of CNS trauma and neurodegenerative diseases, both in vitro and in vivo. Specifically, in the rat optic nerve crush model, autophagy is dramatically activated, but impaired retrograde transport results in the accumulation of autophagosomes as well as increased cellular materials that need degradation; moreover, the lysosomal degradative capacity is also damaged. Although the retrograde mobility of autophagosomes was reduced, it seems not to affect the fusion with other vesicles in the autophagic pathway. Mechanistically, the significant reduction of p150Glued may contribute to the severe impairment of retrograde transport in this model, which may represent a potential therapeutic target for traumatic and neurodegenerative diseases of the central nervous system.
Keywords: axonal degeneration; autophagy; aging; glaucoma and axonal transport
Schlagwörter: axonal degeneration; autophagy; aging; glaucoma and axonal transport