👤 Dominique Lévesque

Biological aging can be described as accumulative, prolonged metabolic stress and is the major risk factor for cognitive decline and Alzheimer's disease (AD). Recently, we identified and described a quinone reductase 2 (QR2) pathway in the brain, in which QR2 acts as a removable memory constraint and metabolic buffer within neurons. QR2 becomes overexpressed with age, and it is possibly a novel contributing factor to age-related metabolic stress and cognitive deficit. We found that, in human cells, genetic removal of QR2 produced a shift in the proteome opposing that found in AD brains while simultaneously reducing oxidative stress. We therefore created highly specific QR2 inhibitors (QR2is) to enable evaluation of chronic QR2 inhibition as a means to reduce biological age-related metabolic stress and cognitive decline. QR2is replicated results obtained by genetic removal of QR2, while local QR2i microinjection improved hippocampal and cortical-dependent learning in rats and mice. Continuous consumption of QR2is in drinking water improved cognition and reduced pathology in the brains of AD-model mice (5xFAD), with a noticeable between-sex effect on treatment duration. These results demonstrate the importance of QR2 activity and pathway function in the healthy and neurodegenerative brain and what we believe to be the great therapeutic potential of QR2is as first-in-class drugs. Show less

Membrane trafficking is defined as the vesicular transport of proteins into, out of, and throughout the cell. In intestinal enterocytes, defects in endocytic/recycling pathways result in impaired function and are linked to diseases. However, how these trafficking pathways regulate intestinal tissue homeostasis is poorly understood. Using the Show less

Prostate cancer is a heterogeneous genetic disease, and molecular methods for predicting prognosis in patients with aggressive form of the disease are urgently needed to better personalize treatment approaches. The objective was to identify host genetic variations in candidate steroidogenic genes affecting hormone levels and prostate cancer progression. The study examined two independent cohorts composed of 526 Caucasian men with organ-confined prostate cancer and 601 Taiwanese men on androgen-deprivation therapy. Caucasians were genotyped for 109 haplotype-tagging single-nucleotide polymorphisms (SNP) in CYP17A1, ESR1, CYP19A1, and HSD3B1, and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings, including previously identified SRD5A1, SRD5A2, HSD17B2, HSD17B3, and HSD17B12 polymorphisms, were then explored in Taiwanese men (n = 32 SNPs). The influence of positive markers on the circulating hormonal levels was then appraised in Caucasians using specific and sensitive mass spectrometry-based methods. After adjusting for known risk factors, variants of CYP17A1 (rs6162), HSD17B2 (rs4243229 and rs7201637), and ESR1 (rs1062577) were associated with progressive disease in both cohorts. Indeed, the presence of these variations was significantly associated with progression in Caucasians (HR, 2.29-4.10; P = 0.0014-2 × 10(-7)) and survival in Taiwanese patients [HR = 3.74; 95% confidence interval (CI): 1.71-8.19, P = 0.009]. Remarkably, the CYP17A1 rs6162 polymorphism was linked to plasma dehydroepiandrosterone-sulfate (DHEA-S) levels (P = 0.03), HSD17B2 rs7201637 with levels of dihydrotestosterone (P = 0.03), and ESR1 rs1062577 with levels of estrone-S and androsterone-glucuronide (P ≤ 0.05). This study identifies, in different ethnic groups and at different disease stages, CYP17A1, HSD17B2, and ESR1 as attractive prognostic molecular markers of prostate cancer progression. Show less

The relationship between polymorphisms in the hydroxysteroid (17-beta) dehydrogenase (HSD17B) family of genes, which are involved in steroid hormone biotransformation, and the risk of prostate cancer (PCa) progression remains unexplored. Determine whether inherited variations in HSD17B genes are associated with PCa progression. We studied two independent Caucasian cohorts composed of 526 men with organ-confined PCa and 213 men with advanced disease who had a median follow-up of 7.4 yr and 7.8 yr after surgery, respectively. Patients with localised PCa were genotyped for 88 haplotype-tagging single nucleotide polymorphisms in HSD17B type 1 (HSD17B1), type 2 (HSD17B2), type 3 (HSD17B3), type 4 (HSD17B4), type 5 (HSD17B5), and type 12 (HSD17B12), and their prognostic significance on disease progression was assessed using Kaplan-Meier survival curves and Cox regression models. Positive findings were then investigated in advanced disease. After adjusting for known risk factors, 12 SNPs distributed across HSD17B2, HSD17B3, and HSD17B12 were significantly associated with risk of biochemical recurrence (BCR) in localised PCa (for variants in HSD17B2: hazard ratio [HR]: 1.92-2.93; p=0.025-0.004). In addition, four variants of HSD17B2 (rs1364287, rs2955162, rs1119933, rs9934209) were significantly associated with progression-free survival (HR: 2.96-4.69; p=0.004-0.00005) and overall survival in advanced disease (HR: 3.98-8.14; p=0.003-0.00002). Four variants of HSD17B3 and HSD17B12 were associated with a reduced risk of BCR (HR: 0.51-0.65; p=0.020-0.036) but not with progression in advanced disease. These results were generated mainly in Caucasians and should be studied in other ethnic groups. This study suggests a prominent role for common genetic variants in the HSD17B2 pathway in PCa progression. Show less