Bavykina, V. | Search bioRxiv

bioRxiv2023

Tracking the progression of Alzheimer's disease with peripheral blood monocytes

BackgroundAlzheimers disease (AD) is the most common form of dementia with the symptoms gradually worsening over the years. However, the driving pathological processes occur well before the appearance of symptoms. AD patients display signs of systemic inflammation, suggesting that it could precede the well-established AD hallmarks. We recently showed that the innate immune response in the form of monocyte activation is detectable at the pre-clinical stage. ObjectivesOur goal here is to characterize changes of gene expression in peripheral blood monocytes from patients at different stages of AD progression and validate potential biomarkers for a better prognosis and diagnosis of AD clinical spectrum. ResultsWe performed a whole transcriptome analysis on monocytes purified from healthy subjects, Mild Cognitive Impairment (MCI) and AD patients, and established the list of genes differentially expressed in monocytes during the disease evolution. We observed that, in the top 500 genes differentially expressed, a majority of these genes were upregulated (65%) during AD progression. These genes are mainly involved in chemokine/cytokine-mediated signaling pathways. We further confirmed several biomarkers by quantitative PCR and immunoblotting and showed that they are often deregulated at pre-clinical stages of the disease (MCI stage), supporting the hyperactivation of monocytes in MCI patients. PerspectivesOur findings provide evidence that the pre-clinical stage of AD can be detected in monocytes using a specific set of biomarkers, highlighting the importance to study the early innate immune response in AD. Our results open the possibility to use these biomarkers with different diagnostic methodologies to better predict and efficiently treat AD.

neuroscience↗

bioRxiv2022

Functional characterization of a PHF8 processed pseudogene in the mouse genome

The majority of pseudogenes are generated when an RNA transcript is reverse-transcribed and integrated into the genome at a new location. Pseudogenes are often considered as an imperfect and silent copy of a functional gene because of the accumulation of numerous mutations in their sequence. Here we report the presence of PHF8-ps, a PHF8 retrotransposed pseudogene in the mouse genome, which has no disruptions in its coding sequence. We showed that this pseudogene was specifically transcribed in testis and can produce a Phf8-ps protein in vivo. As Phf8-ps protein has a well-conserved JmjC domain, we characterized its enzymatic activity and showed that Phf8-ps did not have the intrinsic capability to demethylate H3K9me2 in vitro compared to the parental Phf8 protein. Surprisingly, Phf8-ps did not localize in the nucleus like Phf8 but rather was mostly located at the cytoplasm. Finally, our proteomic analysis of Phf8-ps associated proteins revealed that Phf8-ps interacted with mitochondrial proteins but also with prefoldin subunits (PFDN proteins) that deliver unfolded proteins to the cytosolic chaperonin complex implicated the folding of cytosolic proteins. Together, our findings highlighted Phf8-ps as a new pseudogene-derived protein with distinct molecular functions from Phf8.

biochemistry↗