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McPhie, Donna

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McPhie

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McPhie, Donna

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2007 - 200912010 - 20173

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Author's Publications: search.filters.isAuthorOfPublication.4dc823af-60d2-4db4-b983-c3a28212236c

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Now showing 1 - 4 of 4
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    Functional implications of a psychiatric risk variant within CACNA1C in induced human neurons
    (2014) Yoshimizu, Takao; Pan, Jen Q.; Mungenast, Alison E.; Madison, Jon M.; Su, Susan; Ketterman, Josh; Ongur, Dost; McPhie, Donna; Cohen, Bruce; Perlis, Roy; Tsai, Li-Huei
    Psychiatric disorders have clear heritable risk. Several large-scale genome-wide association studies have revealed a strong association between susceptibility for psychiatric disorders, including bipolar disease, schizophrenia, and major depression, and a haplotype located in an intronic region of the L-type voltage gated calcium channel (VGCC) subunit gene CACNA1C (peak associated SNP rs1006737), making it one of the most replicable and consistent associations in psychiatric genetics. In the current study, we used induced human neurons to reveal a functional phenotype associated with this psychiatric risk variant. We generated induced human neurons, or iN cells, from more than 20 individuals harboring homozygous risk genotypes, heterozygous, or homozygous non-risk genotypes at the rs1006737 locus. Using these iNs, we performed electrophysiology and quantitative PCR experiments that demonstrated increased L-type VGCC current density as well as increased mRNA expression of CACNA1C in induced neurons homozygous for the risk genotype, compared to non-risk genotypes. These studies demonstrate that the risk genotype at rs1006737 is associated with significant functional alterations in human induced neurons, and may direct future efforts at developing novel therapeutics for the treatment of psychiatric disease.
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    Sprouty2 in the Dorsal Hippocampus Regulates Neurogenesis and Stress Responsiveness in Rats
    (Public Library of Science, 2015) Dow, Antonia L.; Lin, Tiffany V.; Chartoff, Elena; Potter, David; McPhie, Donna; Van’t Veer, Ashlee V.; Knoll, Allison T.; Lee, Kristen N.; Neve, Rachael L.; Patel, Tarun B.; Ongur, Dost; Cohen, Bruce; Carlezon, William
    Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders.
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    APP-BP1 Inhibits Aβ42 Levels by Interacting with Presenilin-1
    (BioMed Central, 2007) Chen, Yuzhi; Bodles, Angela M; McPhie, Donna; Neve, Rachael L; Mrak, Robert E; Griffin, W Sue T
    Background: The β-amyloid precursor protein (APP) is sequentially cleaved by the β- and then γ-secretase to generate the amyloid β-peptides Aβ40 and Aβ42. Increased Aβ42/Aβ40 ratios trigger amyloid plaque formations in Alzheimer's disease (AD). APP binds to APP-BP1, but the biological consequence is not well understood. Results: We report that when the endogenous APP-BP1 was suppressed by small interfering RNAs (siRNAs), cell-associated Aβ42 was dramatically increased in APP695 expressing primary neurons. The accumulation of Aβ42 was accompanied by significant increases in APP and APP-CTF in APP-BP1 siRNA expressing neurons. In contrast, APP-BP1 overexpression in primary neurons significantly decreased the levels of Aβ and endogenous APP but not APLPs. We also investigated the potential mechanism of APP-BP1-mediated APP processing. APP-BP1 co-precipitated with Presenilin-1 (PS1) in native rat brain extracts, co-migrated with the γ-secretase components in brain membrane extracts in glycerol gradient centrifugation, and colocalized in primary neurons. Further, the endogenous PS1-CTF was significantly downregulated by APP-BP1 expression. Conclusion: Our data suggest that APP-BP1 may inhibit Aβ42 production by interacting with PS1 under physiological conditions.
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    Late-onset Alzheimer’s disease is associated with inherent changes in bioenergetics profiles
    (Nature Publishing Group UK, 2017) Sonntag, Kai-C.; Ryu, Woo-In; Amirault, Kristopher M.; Healy, Ryan A.; Siegel, Arthur; McPhie, Donna; Forester, Brent; Cohen, Bruce
    Body-wide changes in bioenergetics, i.e., energy metabolism, occur in normal aging and disturbed bioenergetics may be an important contributing mechanism underlying late-onset Alzheimer’s disease (LOAD). We investigated the bioenergetic profiles of fibroblasts from LOAD patients and healthy controls, as a function of age and disease. LOAD cells exhibited an impaired mitochondrial metabolic potential and an abnormal redox potential, associated with reduced nicotinamide adenine dinucleotide metabolism and altered citric acid cycle activity, but not with disease-specific changes in mitochondrial mass, production of reactive oxygen species, transmembrane instability, or DNA deletions. LOAD fibroblasts demonstrated a shift in energy production to glycolysis, despite an inability to increase glucose uptake in response to IGF-1. The increase of glycolysis and the abnormal mitochondrial metabolic potential in LOAD appeared to be inherent, as they were disease- and not age-specific. Our findings support the hypothesis that impairment in multiple interacting components of bioenergetic metabolism may be a key mechanism contributing to the risk and pathophysiology of LOAD.