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

      Maulik, Malabika; Bult-Ito, Abel; Taylor, Barbara E.; Duffy, Lawrence; Kuhn, Thomas; Dunlap, Kriya (2018-12)
      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.
    • Role of neurotropism in HIV-1 gp120 induced oxidative stress and neurodegeneration

      Smith, Lisa K.; Kuhn, Thomas; Kullberg, Max; Dunlap, Kriya; Chen, Jack (2020-05)
      An estimated 50% of individuals with long-term HIV infection are affected by the onset of progressive neurological and cognitive complications referred to as HIV-associated neurocognitive disorders (HAND). While the molecular mechanisms underlying pathology in HAND remain poorly understood, synaptodendritic damage has emerged as a hallmark of HIV infection of the CNS. This damage is likely mediated by a combination of indirect mechanisms involving the release of inflammatory mediators and viral proteins from infected glial cells, and direct effects mediated by the interaction of neurotoxic viral proteins with neuronal receptors. The neurotoxic HIV envelope glycoprotein gp120 interacts with neuronal receptors CCR5 and CXCR4 to induce the coalescence of lipid raft domains into large, stable platforms-- a proposed mechanism for clustering components of receptor-activated signaling cascades. The interaction of proteins with lipid-raft localized receptors as a mechanism of regulating pathologic signaling has been observed in other neurodegenerative diseases, most notably in Alzheimer's disease, where amyloid- (Aß) oligomers interact with lipid raft-anchored cellular prion protein PrPC to activate a pathway leading to the formation of cofilin-actin rods-like inclusions (rods) in neuronal processes. Rods have been linked to synaptic dysfunction via sequestration of cofilin and the disruption of vesicular transport resulting from the occlusion of neurites in which they form. Given similarities in neuronal response to gp120 and Aß, we sought to assess the ability of gp120 to induce rods. Here, we report viral envelope protein gp120 induces the formation of cofilin-actin rods in E16 mouse hippocampal neurons via a signaling pathway common to oligomeric, soluble amyloid-ß and inflammatory cytokines. Our studies demonstrate gp120 binding to either chemokine co-receptor CCR5 or CXCR4 is capable of inducing rod formation and signaling through this pathway requires the NADPH oxidase-mediated formation of superoxide (O2-) and the expression of cellular prion protein (PrPC). These results link gp120-mediated oxidative stress formation to the generation rods in a previously undescribed mechanism of early synaptic dysfunction observed in HAND.