Biology subjects

Horvat, A.

Publications and source records attributed to Horvat, A..

3 recordsLinked to original sources

bioRxiv2026

Restoration of (nor)adrenergic-like Ca2+ signalling counteracts age-related motor decline

Aging disrupts neural function, but whether impaired noradrenergic control of brain metabolism contributes to functional decline remains unclear. Using genetically encoded fluorescent sensors we measured metabolic and signaling responses in neurons and glia of living Drosophila brains following stimulation with octopamine, the invertebrate analogue of noradrenaline. Aging was accompanied by neurodegeneration, reduced locomotion and enhanced oxidative whole-brain metabolism. Octopamine increased D-glucose uptake selectively in astrocytes and elevated L-lactate in both astrocytes and neurons, consistent with astrocytic glycolysis coupled to neuronal L-lactate uptake; monocarboxylate transporter inhibition caused selective astrocytic L-lactate accumulation. In aged animals octopamine-evoked metabolic responses in astrocytes and neural Ca2+ transients were markedly reduced. This impairment was associated with lower expression of adrenoceptor-like tyramine 1 receptor (Tyr1R). Selective Tyr1R overexpression in (nor)adrenergic-like Tdc2 neurons prolonged lifespan, restored Ca2+ signalling and improved locomotor performance. These findings identify Tyr1R-dependent Ca2+ signalling as an age-sensitive regulator of brain metabolism and motor function.

neuroscience↗

bioRxiv2025

Ketamine inhibition of SARS-CoV-2 replication in astrocytes is associated with COVID-19 disease severity in a variant-dependent manner

Severe coronavirus infections, including SARS-CoV-2, can cause neurological symptoms, but the underlying neurotropic mechanisms are unclear. Experiments with SARS-CoV-2 variants B.1.258.17, B.1.1.7, and BA.5.3.2 (termed wild-type, alpha and omicron, respectively) revealed that human astrocytes, not neurons, support viral proliferation. During the COVID-19 pandemic, new virus variants exhibited milder disease progression. A retrospective study of patients with COVID-19 infected by wild-type or alpha variants was conducted to test whether ketamine, an anaesthetic that inhibits endocytosis, affects COVID-19. At admission, patients infected with the wild-type showed greater disease severity than alpha variant patients, but the disease course was similar. This may be due to distinct ketamine-mediated SARS-CoV-2 variant-dependent effects, revealing stronger ketamine inhibition of the wild-type variant than the alpha variant mediating astrocyte responses involving the expression of ACE2, a viral cell entry site, viral proteins RNA-dependent RNA polymerase and envelope protein-E in infected cells. Overexpression of SARS-CoV-2 protein 3a attenuated astroglial lysosomal traffic, and 3a and nsp6 differentially modulated lipid droplet accumulation and initiation of autophagy, where ketamine predominantly affected vesicle dynamics. In summary, human astrocytes, but not neurons, contribute to SARS-CoV-2 neurotropism, highlighting the potential benefits of ketamine treatment in coronavirus infections.

neuroscience↗

bioRxiv2021

Reciprocal regulation of p21 and Chk1 controls the Cyclin D1-RB pathway to mediate senescence onset after DNA damage-induced G2 arrest

Senescence is an irreversible proliferation withdrawal that can be initiated after DNA damage-induced cell cycle arrest in G2 phase to prevent genomic instability. Senescence onset in G2 is not well understood; it requires p53 and RB family tumour suppressors, but how they are regulated to convert a temporary cell cycle arrest into a permanent one remains unknown. Here, we show that a previously unrecognised balance between the CDK inhibitor p21 and Chk1 controls D-type cyclin-CDK activity during G2 arrest. In non-transformed cells, p21 activates RB in G2 by inhibiting Cyclin D1-CDK2/CDK4. The resulting G2 exit, which precedes appearance of senescence markers, is associated with a mitotic bypass, Chk1 inhibition and DNA damage foci reduction. In p53/RB-proficient cancer cells, compromised G2 exit correlates with sustained Chk1 activity, delayed p21 induction, untimely Cyclin E1 re-expression and genome reduplication. Chk1 depletion promotes cell cycle exit by inducing p21 binding to Cyclin D1 and Cyclin E1-CDK complexes and down-regulating CDK6, whereas Chk2 knockdown promotes RB phosphorylation and delays G2 exit. In conclusion, p21 and Chk2 oppose Chk1 to maintain RB activity, thus controlling DNA damage-induced senescence onset in G2.

cell biology↗