Hepatoma-derived growth factor is neuroprotective in models of Huntington's disease

Völkl, Kerstin (2022): Hepatoma-derived growth factor is neuroprotective in models of Huntington's disease. Dissertation, LMU München: Faculty of Biology

Abstract

Huntington’s disease (HD) is a fatal hereditary disorder with severe neurodegeneration in the striatum and cortex. Despite the monogenic nature of HD, disease pathogenesis is insufficiently understood and effective disease-modifying treatments are lacking to date. Here, we uncover hepatoma-derived growth factor (HDGF) as a neuroprotective protein in the context of HD. HDGF counteracts mutant huntingtin aggregation and cell death in murine primary cortical neurons. Expression levels of HDGF in mouse brain are inversely correlated with vulnerability of brain regions and individual neuronal populations to HD. In R6/2 HD model mice, HDGF deficiency exacerbates motor defects and reduces life span, while viral HDGF delivery into the nervous system significantly improves locomotor activity. Mechanistic studies in cell culture models of HD demonstrate that the neuroprotective activity of HDGF is independent of its subcellular localization: Nuclear and cytoplasmic HDGF are equally effective in rescuing mutant huntingtin toxicity. Moreover, extracellular application of recombinant HDGF is sufficient to improve viability of mutant huntingtin-expressing primary neurons via a mechanism distinct from canonical growth factor signaling. Taken together, this study provides new insights into HDGF function in the diseased brain and unravels the therapeutic potential of HDGF in HD.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 570 Life sciences
• Faculties: Faculty of Biology
• Language: English
• Date of oral examination: 21. July 2022
• 1. Referee: Klein, Rüdiger
• Signature of the printed copy: 0001/UMC 29722