Biology subjects

Roseman, M.

Publications and source records attributed to Roseman, M..

2 recordsLinked to original sources

bioRxiv2024

Heparan sulfate modified proteins affect cellular processes central to neurodegeneration and modulate presenilin function

Mutations in presenilin-1 (PSEN1) are the most common cause of familial, early-onset Alzheimers disease (AD), typically producing cognitive deficits in the fourth decade. A variant of APOE, APOE3 Christchurch (APOE3ch), was found associated with protection from both cognitive decline and Tau accumulation in a 70-year-old bearing the disease-causing PSEN1-E280A mutation. The amino acid change in ApoE3ch is within the heparan sulfate (HS) binding domain of APOE, and purified APOEch showed dramatically reduced affinity for heparin, a highly sulfated form of HS. The physiological significance of ApoE3ch is supported by studies of a mouse bearing a knock-in of this human variant and its effects on microglia reactivity and A{beta}-induced Tau deposition. The studies reported here examine the function of heparan sulfate-modified proteoglycans (HSPGs) in cellular and molecular pathways affecting AD-related cell pathology in human cell lines and mouse astrocytes. The mechanisms of HSPG influences on presenilin-dependent cell loss and pathology were evaluated in Drosophila using knockdown of the presenilin homolog, Psn, together with partial loss of function of sulfateless (sfl), a homolog of NDST1, a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in cultured human cell lines, Drosophila, and mouse astrocytes. RNAi of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3, and APOE4. RNA-sequence analysis of human cells deficient in HS synthesis demonstrated effects on the transcriptome governing lipid metabolism, autophagy, and mitochondrial biogenesis and showed significant enrichment in AD susceptibility genes identified by GWAS. Neuron-directed knockdown of Psn in Drosophila produced cell loss in the brain and behavioral phenotypes, both suppressed by simultaneous reductions in sfl mRNA levels. Abnormalities in mitochondria, liposome morphology, and autophagosome-derived structures in animals with Psn knockdown were also rescued by simultaneous reduction of sfl. sfl knockdown reversed Psn-dependent transcript changes in genes affecting lipid transport, metabolism, and monocarboxylate carriers. These findings support the direct involvement of HSPGs in AD pathogenesis.

neuroscience↗

bioRxiv2022

Processing of Different Social Scales in the Human Brain

For an individual to lead a healthy and fulfilling social life, it is essential to have relationships with multiple people who are at different levels of emotional closeness. Based on ethological, sociological and psychological evidence, social networks have been divided into five scales of emotional closeness, gradually increasing in size and decreasing in emotional proximity. Is this division also reflected in different brain processes? During functional MRI, participants compared their emotional closeness to different members of their social network. We examined the brain area that was differentially activated for levels of emotional closeness, and found that its vast majority (78%) showed preference for people who are closest to participants, including the temporoparietal junction, middle temporal gyrus, precuneus and dorsomedial prefrontal cortex. A different system, which includes the medial temporal lobe, retrosplenial cortex and ventromedial prefrontal cortex showed preference for all other social scales. Moreover, we found a significant correlation between brain responses to emotionally close people and smaller spaces (room, building) as well as between emotionally distant people and larger spaces (neighborhood, city). Finally, brain activity at the default mode network (DMN) was associated with social scale preference, such that its subnetwork DMN A, related to social processing, showed preference to closer social scales, while DMN C, related to spatiotemporal processing, showed preference to farther social scales. Our results show that the cognitive processing of a few intimately close people differs from the rest of the social network, emphasizing their crucial role in social life. SignificanceWe divide the people in our lives according to levels of emotional closeness, called social scales, ranging from the few people who are the closest to us, in which we invest most of our social efforts and time (support clique), to the farthest level of [~]150 acquaintances. Here, we used neuroimaging to investigate the brain processing of different social scales. We found that the area of cortex dedicated to the support clique is much larger than that of all other scales and encompasses different brain regions. Interestingly, this division is similar to the one between processing of small and larger spaces, and processed by different subregions of the default mode network. Our study emphasizes the importance of close relationships in our social lives as found in the brain.

neuroscience↗