Biology subjects

Lalowski, M.

Publications and source records attributed to Lalowski, M..

4 recordsLinked to original sources

bioRxiv2024

CX3CR1 modulates migration of resident microglia towards brain injury

Microglia are innate immune cells of the central nervous system (CNS). They extend their processes towards and migrate towards injuries in vivo. However, whether the fractalkine receptor (CX3CR1) influences microglial migration remains unknown. Label-free proteomic profiling predicted changes in RHO-signaling activity that hint at dysregulated cytoskeleton signaling in Cx3cr1-deficient murine cortex tissue. To further investigate microglial migration, we carried out 4-hour interval two-photon in vivo imaging for 72 hours after a laser lesion in the cortex. Cx3cr1-deficient microglia showed enhanced migration towards the lesion. Additionally, length and velocity of microglial fine processes extending towards the lesion were increased in Cx3cr1-deficient microglia. Migration remained unchanged in Ccr2-deficient mice, indicating that monocyte-derived macrophages/microglia did not contribute to microglia accumulation around the lesion. These results demonstrate microglia migration towards CNS injury and suggest CX3CR1 as a modulator of this. Manipulating microglia migration via CX3CR1 therefore is a potential target for treatment of CNS-injury.

neuroscience↗

bioRxiv2024

USP14 regulates pS129 α-synuclein levels and oxidative stress in human SH-SY5Y dopaminergic cells

Ubiquitin specific protease-14 (USP14) is critical for controlling protein homeostasis disturbed in human disorders like Parkinso[n]s disease (PD). Here we investigated the role of USP14 in regulating proteasome and autophagy pathways, and their influence on -synuclein (-syn) degradation. Data showed that -syn and phosphorylated serine129 -syn (pS129 -syn) were elevated in USP14 gene-deleted SH-SY5Y dopaminergic cells with concomitant reduction in proteasome activity. Inhibition of proteasomes using MG132 particularly elevated pS129 -syn in these cells, but the levels were not influenced by inhibiting autophagy using chloroquine. In contrast, autophagy and the CLEAR (Coordinated Lysosomal Expression and Regulation) pathways were elevated in USP14 lacking cells with an upregulation of the transcription factor TFEB. USP14-ablated cells also exhibited increases in reactive oxidative species (ROS) and elongation of mitochondria. The addition of N-Acetylcysteine amide (NACA) to counteract oxidative stress, reduced pS129 -syn and -syn levels in USP14 deficient cells. Phospho-proteomic analyses revealed that USP14 is phosphorylated at S143 affecting its function and structure as shown by molecular modeling, and protein interaction studies. Re-expression of wild-type and the phospho-mimetic S143D-USP14 mutant decreased ROS, pS129 -syn, and -syn in USP14 lacking cells. These results demonstrate that pS129 -syn levels are sensitive to oxidative stress in SH-SY5Y dopaminergic cells. USP14 by stimulating the proteasome activity and reducing oxidative stress is a promising factor for targeting -syn and its pathogenic variants in PD.

neuroscience↗

bioRxiv2024

Menopause-associated proteomic and lipidomic alterations in high-density lipoprotein: Perimenopause is characterized by smaller triacylglycerols-enriched particles.

High-density lipoprotein particles (HDL) possess anti-inflammatory, anti-thrombotic, cytoprotective, and anti-oxidative properties, thus protecting against cardiovascular diseases. Menopause is associated with changes in serum metabolome and HDL size distribution. We analyzed the protein and lipid composition of the HDL particles from pre-, peri-, and postmenopausal women (N=216) with nuclear magnetic resonance and mass spectrometry to get a deeper insight into the composition of HDL in different stages of menopause. Both particle size and composition differed; in perimenopause, the proportion of small HDL particles (8.7 nm on average) was higher, and the proportion of large HDL particles (12.1 nm on average) was lower than in pre- or postmenopause. In perimenopause, each particle size class was enriched with triacylglycerols, and the calculated lipid class ratio of triacylglycerol/cholesteryl ester was the highest within perimenopausal HDL particles. This potentially affects the HDL interaction with lipid-modifying enzymes. We also observed directionally opposite associations for HDL cholesteryl ester and unesterified cholesterol with systemic estradiol and follicle-stimulating hormone levels, especially regarding S-sized HDL particles, but not the hormone associations with HDL triacylglycerols. Perimenopausal HDL also exhibited a lower proportion of apolipoproteins (apoA-I, apoA-II, apoC-I, apoC-III, apoD and apoE) per particle than premenopausal or postmenopausal HDL. In summary, we found that premenopausal and postmenopausal HDL particles were compositionally similar and differed from perimenopausal ones. We suggest that menopause, and especially the unbalanced hormonal state in perimenopause, are reflected in the lipid and protein compositions of the HDL, which, in turn, may affect the functions of the HDL particle.

molecular biology↗

bioRxiv2023

Ketogenic diet alters microglial morphology and changes the hippocampal lipidomic profile distinctively in stress susceptible versus resistant male mice upon repeated social defeat

Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress. HighlightsO_LIKetogenic diet tends to promote resistance to psychological stress C_LIO_LIHippocampal microglia show morphological adaptations to stress and diet C_LIO_LIMicroglia of stress-susceptible mice make less synaptic contacts C_LIO_LIMicroglia of ketogenic diet-fed mice show less signs of cellular stress C_LIO_LILipids are differentially regulated in the hippocampi of susceptible mice C_LI

neuroscience↗