Biology subjects

Patterson, C.

Publications and source records attributed to Patterson, C..

3 recordsLinked to original sources

bioRxiv2018

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of cerebellar CHIPopathy

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. Mutations in CHIP are the driver of spinocerebellar autosomal recessive 16 (SCAR16), or cerebellar CHIPopathy, as we initially discovered this disease was caused by a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrate that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and alters the co-chaperone function of CHIP. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.

animal behavior and cognition↗

bioRxiv2018

TAS2R38 predisposition to bitter taste associated with differential changes in vegetable intake in response to a community-based dietary intervention

BackgroundAlthough vegetable consumption is associated with decreased risk for a variety of chronic diseases, few Americans meet the CDC recommendations for vegetable intake. The TAS2R38 gene encodes a taste receptor that confers bitter taste sensing from chemicals found in some vegetables. Common polymorphisms in TAS2R38, including rs713598, rs1726866, and rs10246939, lead to coding substitutions that alter receptor function and result in the loss of bitter taste perception.\n\nObjectiveOur study examines whether bitter taste perception TAS2R38 diplotypes were associated with vegetable consumption in participants enrolled in either an enhanced or a minimal nutrition counseling intervention within a community-based dietary intervention.\n\nMethodsDNA was isolated from the peripheral blood cells of study participants (N = 497) and analyzed for polymorphisms using genotyping arrays. The Block Fruit and Vegetable screener was used to determine frequency of vegetable consumption. Mixed effects models were used to test differences in frequency of vegetable consumption between intervention and genotype groups over time.\n\nResultsThere was no association between baseline vegetable consumption frequency and the bitter taste diplotype (p = 0.937), however after six months of the intervention, we observed an interaction between bitter taste diplotypes and time (p = 0.046). Participants in the enhanced intervention increased their vegetable consumption frequency (p = 0.020) and within this intervention group, the non-bitter and intermediate-bitter tasting participants had the largest increase in vegetable consumption. In contrast, in the minimal intervention group, the bitter tasting participants reported a decrease in vegetable consumption.\n\nConclusionsNon- and intermediate-bitter taste blind participants increased vegetable consumption in either intervention group more than those who perceive bitterness. Future applications of precision medicine could consider genetic variation in bitter taste perception genes when designing dietary interventions.\n\nAuthor summaryMost Americans under consume vegetables, despite clear associations between vegetable consumption and health benefits. Vegetables, such as broccoli, kale, and Brussels sprouts, contain bitter-tasting compounds, leading to taste aversion. Common polymorphisms on the TAS2R38 taste receptor gene (rs713598, rs1726866, and rs10246939) influence the perception of bitter taste. We tested whether genetic predisposition to bitter taste influenced vegetable intake in a dietary intervention and found that TAS2R38 diplotypes were related to vegetable consumption. Combining precision medicine approaches that identify taste profiles and personalizing dietary advice could help engage intervention participants and improve the impact of dietary interventions.

genomics↗

bioRxiv2017

Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes through Defects in Microtubule Polymerization and Glucose Transporter Localization

Recent evidence has implicated CHIP (carboxyl terminus of Hsc/Hsp70-interacting protein), a co-chaperone and ubiquitin ligase, in the functional support of several metabolism-related proteins, including AMPK and SirT6. In addition to previously reported aging and stress intolerance phenotypes, we find that CHIP -/- mice also demonstrate a Type II diabetes-like phenotype, including poor glucose tolerance, decreased sensitivity to insulin, and decreased insulin-stimulated glucose uptake in isolated skeletal muscle, characteristic of insulin resistance. In CHIP-deficient cells, glucose stimulation fails to induce translocation of Glut4 to the plasma membrane. This impairment in Glut4 translocation in CHIP-deficient cells is accompanied by decreased tubulin polymerization associated with decreased phosphorylation of stathmin, a microtubule-associated protein required for polymerization-dependent protein trafficking within the cell. Together, these data describe a novel role for CHIP in regulating microtubule polymerization that assists in glucose transporter translocation, promoting whole-body glucose homeostasis and sensitivity to insulin.

physiology↗