Role of dietary fat and supplementation in modulating neurodegenerative pathology in two animal model systems

Abstract

Neurodegenerative disorders are progressive conditions that worsen over time and results in death of neurons. Parkinson's disease (PD) is a prevalent example of one such age-related disease, which is characterized by movement disorder (ataxia) and/or cognitive disability (dementia). Pathologically, PD is characterized by a toxic accumulation of α-synuclein protein in the midbrain leading to degeneration of the dopaminergic neurons. The etiology of PD is intricate, and the cause is attributed to genetic mutations and environmental factors like insecticides or heavy metals. Moreover, treatment options are limited and often aimed at treating the symptoms rather than the actual disease progression. Using the nematode model of Caenorhabditis elegans, I examined the effect of Alaskan bog blueberry (Vaccinium uliginosum) on α-synuclein overexpression and how such indigenous natural treatment can modulate key molecular targets like sirtuins, which are proteins involved in regulating cellular processes including aging, death and their resistance to stress. The impact of extrinsic factors like dietary fat on PD pathology has been sparsely explored and the molecular basis of such changes is not known. Through my thesis research, I also further investigated the influence of fat metabolism on key hallmarks of PD: α-synuclein overexpression and dopaminergic degeneration in the nematode model. Finally, I studied the interaction of dietary fat (normal, low and high fat) and Alaskan blueberry supplementation on metal induced neurotoxicity model of Mus musculus. Our results highlight the beneficial properties of Alaskan blueberries in combating proteotoxic stress and inflammation in both animal models. They also reiterate the benefit of low fat diet, on its own or in combination with supplementation in improving several PD-like molecular features and how consuming high fat can mask such health promoting outcomes. The current thesis work therefore, provides a foundation for further exploration of neurobiological changes associated with consumption of natural products and different diets and how such alterations can be extrapolated to humans.