Huntington Disease (HD) is a neurodegenerative disorder pathologically characterized by selective degeneration of neurons within the striatum, cortex and hypothalamus. HD is caused by a CAG repeat expansion within the HTT gene, with longer repeats being strongly associated with earlier age-of-onset. Although repeat length explains over half of the variability in age of onset, a landmark genetic study attributed the majority of residual variability to unknown environmental factors. Metal ions with neurotoxic properties are strong candidates for environmental agents that may modulate selective neurodegenerative process like HD because, (1) the differential accumulation of various metals across neuronal subtypes, (2) the similarities between metal ion cytotoxicity and cellular pathways of neurodegeneration, and (3) our research in the previous funding cycle demonstrating altered vulnerability in mouse models of HD to both manganese and cadmium. The long-term goal of this research program is to reveal the pathogenic mechanisms underlying gene-environment interactions in neurodegenerative disease, focusing on HD given its clearly defined genetic etiology, to inform environmental health strategies to delay disease onset or slow the progression of disease. Our highly innovative approach combines (a) a novel high-throughput method to quantify cellular Mn status, (b) a state-of-the-art high throughput screen (HTS) facility at the Vanderbilt Institute of Chemical Biology (VICB), and (c) the clinical relevance of a patient-specific neuronal model system based on human induced pluripotent stem cell (hiPSC) technology.
Aim 1 will test the hypothesis that an HD striatal Mn handling deficit discovered in the previous funding cycle will enable a HTS to find small molecules that mitigate the actions of HD environmental risk factors.
Aim 2 will test the hypothesis that human striatal neuroprogenitors (NPs) from HD patients have increased sensitivity to non-cytotoxic levels of metal toxicants impinging upon specific stress response pathways.
Aim 3 will test the clinical potential of small molecule modifiers of environmental risk factors in HD and whether the magnitude of HD-specific toxicant vulnerability will correlate by patient with established disease-modifiers such as neural lineage specificity, CAG-repeat length and clinical variation in age-of-onset.
These specific aims will reveal disease-relevant environmental stress responses and identify small molecules to mitigate vulnerabilities and restore neuronal homeostasis in HD. Furthermore, discovery of toxicant interactions and patient-specific responses may inform environmental health strategies to delay disease onset or slow the progression of HD using a personalized medicine approach.
The proposed studies will (1) evaluate p53 and AKT/mTOR cell stress signaling pathways as mediators of gene-environment interactions in Huntington disease (HD), (2) test whether human striatal neuroprogenitors derived from HD patients will exhibit selective vulnerability to Mn and other neurotoxicants that impinge upon these specific stress response pathways, (3) validate the pathogenic relevance of these pathways in an in vivo HD mouse model, and (4) determine if patient variation in HD age-of-onset correlates with sensitivity to HD- relevant neurotoxicants. Our multidisciplinary approach seeks to define the functional domains that underlie modulation of HD by environmental risk factors and identify the clinical correlates of the stress response pathways that underlie this neurodegenerative disease.
|Bryan, Miles R; Bowman, Aaron B (2017) Manganese and the Insulin-IGF Signaling Network in Huntington's Disease and Other Neurodegenerative Disorders. Adv Neurobiol 18:113-142|
|Di Pardo, Alba; Amico, Enrico; Basit, Abdul et al. (2017) Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease. Sci Rep 7:5280|
|Pfalzer, Anna C; Bowman, Aaron B (2017) Relationships Between Essential Manganese Biology and Manganese Toxicity in Neurological Disease. Curr Environ Health Rep 4:223-228|
|Hollmann, Emma K; Bailey, Amanda K; Potharazu, Archit V et al. (2017) Accelerated differentiation of human induced pluripotent stem cells to blood-brain barrier endothelial cells. Fluids Barriers CNS 14:9|
|Bryan, Miles R; Uhouse, Michael A; Nordham, Kristen D et al. (2017) Phosphatidylinositol 3 kinase (PI3K) modulates manganese homeostasis and manganese-induced cell signaling in a murine striatal cell line. Neurotoxicology :|
|Bichell, Terry Jo V; Wegrzynowicz, Michal; Tipps, K Grace et al. (2017) Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model. Biochim Biophys Acta 1863:1596-1604|
|Armstrong, Laura C; Westlake, Grant; Snow, John P et al. (2017) Heterozygous loss of TSC2 alters p53 signaling and human stem cell reprogramming. Hum Mol Genet 26:4629-4641|
|Brown, Jacquelyn A; Codreanu, Simona G; Shi, Mingjian et al. (2016) Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit. J Neuroinflammation 13:306|
|Osmand, Alexander P; Bichell, Terry Jo; Bowman, Aaron B et al. (2016) Embryonic Mutant Huntingtin Aggregate Formation in Mouse Models of Huntington's Disease. J Huntingtons Dis 5:343-346|
|Tidball, Andrew M; Neely, M Diana; Chamberlin, Reed et al. (2016) Genomic Instability Associated with p53 Knockdown in the Generation of Huntington's Disease Human Induced Pluripotent Stem Cells. PLoS One 11:e0150372|
Showing the most recent 10 out of 45 publications