Neuraminidases as potential therapeutic targets for Parkinson’s disease

Thesis

Neuraminidases are a family of enzymes that remove terminal sialic acid residues from glycoconjugates, including glycoproteins and glycosphingolipids (GSLs). They play critical roles in the metabolism of complex gangliosides, the most abundant GSLs in the mammalian brain, which are involved in cellular homeostasis and signalling. Parkinson’s disease (PD) is characterised by progressive motor and cognitive decline, with its aetiology linked to multiple mechanisms, including lysosomal dysfunction and impaired cellular homeostasis. Notably, over 50 genes encoding lysosomal proteins impaired in rare lysosomal storage disorders (LSDs) have now been identified as PD risk factors. Altered GSL metabolism, linked to lysosomal dysfunction, is a hallmark of both LSDs and PD. One neuroprotective GSL, GM1a, shows a significant age-related decrease in the human brain, with a more pronounced reduction in individuals with PD. In contrast, mice exhibit an age-related increase in GM1a levels and elevated activity of neuraminidases that catabolise gangliosides like GM1a, which are abundant in the mammalian brain. Mice also have an inherently higher basal neuraminidase activity than humans, which may contribute to mice being resistant to developing PD-like pathology.

Based on these findings, we hypothesised that neuraminidases are potential therapeutic targets for PD. We have therefore characterised Neu3 and/or Neu4 knockout mice, as these isoenzymes are critical in converting complex gangliosides into GM1a. These neuraminidase-deficient mice exhibited brain GSL profiles similar to those of aged humans and PD patients. These mice accumulated α-Syn and developed progressive motor deficits as they aged, suggesting their potential use as a model for PD. Finally, we have explored a novel therapeutic strategy targeting Neu3 and Neu4, evaluating the potential efficacy of enzyme enhancement in vitro and in vivo.

Authors: Zhang, Q

• DOI: 10.5287/ora-00dg1zkx0
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: neuraminidases; Neu3; Neu4; GM1a; glycosphingolipid metabolism; Parkinson’s disease
• Subjects: Dissertations, Academic