Biology subjects

Ibrahim, T.

Publications and source records attributed to Ibrahim, T..

3 recordsLinked to original sources

bioRxiv2023

Sex-dependent Differences in the Genomic Profile of Lingual Sensory Neurons in Naive and Tongue-Tumor Bearing Mice

Mechanisms of sex-dependent orofacial pain are widely understudied. A significant gap in knowledge exists about comprehensive regulation of tissue-specific trigeminal sensory neurons in diseased state of both sexes. Using RNA sequencing of FACS sorted retro-labeled sensory neurons innervating tongue tissue, we determined changes in transcriptomic profiles in males and female mice under naive as well as tongue-tumor bearing conditions Our data revealed the following interesting findings: 1) Tongue tissue of female mice was innervated with higher number of trigeminal neurons compared to males; 2) Naive female neurons innervating the tongue exclusively expressed immune cell markers such as Csf1R, C1qa and others, that werent expressed in males. This was validated by Immunohistochemistry. 4) Accordingly, immune cell markers such as Csf1 exclusively sensitized TRPV1 responses in female TG neurons. 3) Male neurons were more tightly regulated than female neurons upon tumor growth and very few differentially expressed genes (DEGs) overlapped between the sexes, 5) Male DEGs contained higher number of transcription factors whereas female DEGs contained higher number of enzymes, cytokines and chemokines. Collectively, this is the first study to characterize the effect of sex as well as of tongue-tumor on global gene expression, pathways and molecular function of tongue-innervating sensory neurons.

neuroscience↗

bioRxiv2022

Telomere-induced senescence increases aberrant intraneuronal amyloid-β accumulation by impairing autophagy in a mouse model of Alzheimer's disease

Aging is a well-known risk factor for Alzheimers disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes occurring in the aging brain are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. In this study, we investigated the role of cellular senescence on AD pathology by crossing an amyloid-{beta} (A{beta}) mouse model of AD (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc-/-). Our results show that accelerated senescence reduces amyloid plaque formation and A{beta} levels at an age when full-blown amyloid pathology is observed in 5xFAD mice. However, early and aberrant intraneuronal A{beta} accumulation is observed in the subiculum and cortical layer V of senescent mice. Selective neurodegeneration linked to telomere attrition and early intraneuronal A{beta} accumulation was observed in these particular regions. Finally, our results suggest that the effect of senescence on amyloid pathology might be mediated through an alteration in autophagy function. Altogether, these findings demonstrate the instrumental role of senescence in intraneuronal A{beta} accumulation associated to AD pathophysiology, and further support future approaches targeting these processes for therapeutic intervention.

neuroscience↗

bioRxiv2022

AF2-multimer guided high accuracy prediction of typical and atypical ATG8 binding motifs

Macroautophagy/autophagy is an intracellular degradation process central to cellular homeostasis and defense against pathogens in eukaryotic cells. Regulation of autophagy relies on hierarchical binding of autophagy cargo receptors and adaptors to ATG8/LC3 protein family members. Interactions with ATG8/LC3 are typically facilitated by a conserved, short linear sequence, referred to as the ATG8/LC3 interacting motif/region (AIM/LIR), present in autophagy adaptors and receptors as well as pathogen virulence factors targeting host autophagy machinery. Since the canonical AIM/LIR sequence can be found in many proteins, identifying functional AIM/LIR motifs has proven challenging. Here we show that protein modelling using Alphafold-Multimer (AF2-multimer) identifies both canonical and atypical AIM/LIR motifs with a high level of accuracy. AF2-multimer can be modified to detect additional functional AIM/LIR motifs by using protein sequences with mutations in primary AIM/LIR residues. By combining protein modelling data from AF2-multimer with phylogenetic analysis of protein sequences and protein-protein interaction assays, we demonstrate that AF2-multimer predicts the physiologically relevant AIM motif in the ATG8-interacting protein 2 (ATI-2) as well as the previously uncharacterized non-canonical AIM motif in ATG3 from potato (Solanum tuberosum). AF2-multimer also identified the AIM/LIR motifs in pathogen-encoded virulence factors that target ATG8 members in their plant and human hosts, revealing that cross-kingdom ATG8-LIR/AIM associations can also be predicted by AF2-multimer. We conclude that the AF2-guided discovery of autophagy adaptors/receptors will substantially accelerate our understanding of the molecular basis of autophagy in all biological kingdoms.

molecular biology↗