👤 Véronik Lachance

Dysfunctional autophagy is implicated in Alzheimer's Disease (AD) pathogenesis. The alterations in the expression of many autophagy related genes (ATGs) have been reported in AD brains; however, the disparity of the changes confounds the role of autophagy in AD. To further understand the autophagy alteration in AD brains, we analyzed transcriptomic (RNAseq) datasets of several brain regions (BA10, BA22, BA36 and BA44 in 223 patients compared to 59 healthy controls) and measured the expression of 130 ATGs. We used autophagy-deficient mouse models to assess the impact of the identified ATGs depletion on memory, autophagic activity and amyloid-β (Aβ) production. We observed significant downregulation of multiple components of two autophagy kinase complexes BECN1-PIK3C3 and ULK1/2-FIP200 specifically in the parahippocampal gyrus (BA36). Most importantly, we demonstrated that deletion of NRBF2, a component of the BECN1-PIK3C3 complex, which also associates with ULK1/2-FIP200 complex, impairs memory in mice, alters long-term potentiation (LTP), reduces autophagy in mouse hippocampus, and promotes Aβ accumulation. Furthermore, AAV-mediated NRBF2 overexpression in the hippocampus not only rescues the impaired autophagy and memory deficits in NRBF2-depleted mice, but also reduces β-amyloid levels and improves memory in an AD mouse model. Our data not only implicates NRBF2 deficiency as a risk factor for cognitive impairment associated with AD, but also support the idea of NRBF2 as a potential therapeutic target for AD. Show less

Glioma is a rare, but highly fatal, cancer that accounts for the majority of malignant primary brain tumors. Inherited predisposition to glioma has been consistently observed within non-syndromic families. Our previous studies, which involved non-parametric and parametric linkage analyses, both yielded significant linkage peaks on chromosome 17q. Here, we use data from next generation and Sanger sequencing to identify familial glioma candidate genes and variants on chromosome 17q for further investigation. We applied a filtering schema to narrow the original list of 4830 annotated variants down to 21 very rare (<0.1% frequency), non-synonymous variants. Our findings implicate the MYO19 and KIF18B genes and rare variants in SPAG9 and RUNDC1 as candidates worthy of further investigation. Burden testing and functional studies are planned. Show less

We performed microarray gene expression analyses on the visual cortex of Old-World monkeys (Cercopithicus aethiops) in an effort to identify transcripts associated with developmental maturation and activity-driven changes during the visual critical period. Samples derived from normal animals and those subjected to monocular enucleation (ME) were hybridized to human Affymetrix HG-U95Av2 oligonucleotide microarrays (N = 12) and the results were independently validated by real-time quantitative RT-PCR. To identify genes exhibiting significant expression differences among our samples, the microarray hybridization data were processed with two software packages that use different analytical models (Affymetrix MicroArray Suite 5.0, dChip 1.2). We identified 108 transcripts within diverse functional categories that differed in their visual cortical expression at the height of the critical period when compared to adults. The expression levels of four transcripts were also globally modulated following ME during the critical period. These transcripts are particularly sensitive to ME during the critical period but are not significantly modulated in ME adults. Three of the ME-driven genes (NGFI-B, egr3, NARP) are known immediate-early genes (IEG) while the other (DUSP6) is a phosphatase that can regulate IEG expression. The putative biological significance of the ME-driven and developmentally regulated genes is discussed with respect to the critical period for activity-dependent visual cortical neuroplasticity. Show less