Biology subjects

Palumaa, T.

Publications and source records attributed to Palumaa, T..

6 recordsLinked to original sources

bioRxiv2026

Model of naturally occurring refractive error (NORE) in mice

PurposeAnimal models of myopia typically induce monocular refractive shifts via form deprivation (FD) or lens-induced myopia (LIM), modeling susceptibility to myopia, but with potentially limited applicability to childhood myopia. Here we describe a novel, genetically diverse mouse model of naturally occurring refractive error (NORE) with three distinct refractive phenotypes: hyperopic, myopic, and intermediate. MethodsC57BL/6J mice were mated to 129S2/SvPasCrl mice to create F1 or F2 offspring. Refractive errors in male and female F1 (N=21) and F2 (N=101) mice were assessed on postnatal days (P) 28 and 42 using photorefractometry. In a subset of mice (N=30-40), corneal radius of curvature, axial ocular dimensions, retinal and visual function were assessed. ResultsF2 mice were classified as NORE with either hyperopic (RE[≥]0 diopters (D) at P28 and P42), myopic (RE<0D at P28 and P42) or intermediate (RE<0D at P28 and RE[≥]0D at P42) refractions based on individual trajectories. All ocular parameters changed with age, with significantly slower growth in axial length and vitreous chamber depth in the intermediate versus myopic mice (p<0.05). Lens thickness was smaller in the myopic group at P28. Differences in refraction were not attributed to variances in retinal function or dopamine signaling. ConclusionsNORE mice represent a novel, genetically diverse wild-type mouse model that, unlike traditional models, does not require interventions such as FD or LIM to induce myopia. NORE mice provide a valuable tool for future investigations of genetic and environmental mechanisms and targeted therapeutic strategies for refractive errors.

genetics↗

bioRxiv2026

Circadian rhythms regulate refractive development across species

Myopia is a rapidly escalating global public health challenge, yet the biological mechanisms linking modern lifestyles to abnormal eye growth remain unclear. Circadian rhythms have been implicated in refractive development, but causal evidence is limited. Here, we integrate population-scale human data with an experimental animal model to determine whether circadian misalignment contributes to myopia. In >265,000 individuals from the Estonian and UK Biobanks, late chronotype was consistently associated with myopia. To assess causality, we experimentally disrupted the alignment between behavioural and environmental rhythms in mice by housing them in non-24-hour light-dark schedules. Exposure to a lengthened cycle (T26) induced a myopic shift that was, notably, reversible in early adulthood. Retinal transcriptomics revealed enrichment of mitochondrial and hypoxia-related plasticity pathways, with transcriptional changes distributed across multiple retinal cell classes. Together, these findings identify circadian misalignment as a conserved and modifiable driver of myopia, highlighting opportunities for novel preventive and therapeutic approaches.

neuroscience↗

bioRxiv2026

Local clocks within human tissues reveal widespread 24-hour rhythms in gene expression

Circadian clocks govern the 24-hour rhythmic activity of organs across the human body and these nycthemeral rhythms are critical for human physical and mental health. Here, we analysed 14,886 samples across 45 human tissues and inferred tissue-specific local phases using CHIRAL to define the rhythmic transcriptome. Local phase inference identified a median of 5,747 rhythmic transcripts across tissues, including 5,531 across brain tissues, indicating that prior donor-level approaches have substantially underestimated the extent of rhythmic transcription in the human brain. In the brain, rhythmic genes were enriched for neurotransmitter pathways, the synaptic vesicle cycle, circadian entrainment and major neurodegenerative disorders. Strikingly, more than 200 genes in Alzheimers, Parkinsons, Huntingtons and prion disease pathways displayed significant 24-hour rhythmicity across cortical, striatal and hippocampal regions, segregating into distinct diurnal and nocturnal phase clusters. These included Parkinsons disease genes SNCA and PRKN, Alzheimers disease genes PSEN1 and APP, prion disease genes PRNP and EIF2AK3 (PERK), and Huntingtons disease genes HTT and GPR52. Among these disease-associated rhythmic transcripts were several targets already under therapeutic investigation for which administration at specific times of day may improve therapeutic efficacy or tolerability. Here, we observe that human tissues, including the brain, exhibit distinct local rhythmic organisation. These findings provide novel insights into disease mechanisms and highlight opportunities for target discovery, drug development and chronotherapeutic intervention.

molecular biology↗

bioRxiv2025

Forced exercise modulates retinal inflammatory response and regulates miRNA expression to promote retinal neuroprotection during degeneration

BackgroundOur labs have demonstrated exercise is protective in animal models of retinal degeneration (RD). Inflammation drives RD progression, and is regulated by the recruitment and reactivity of glia cells as well as through small non-coding RNAs, microRNAs (miRNAs). Here, we explore the effects of treadmill exercise on the recruitment and reactivity of retinal inflammatory cells within the neural retina and miRNA expression in a light-induced retinal degeneration model (LIRD) that exhibits phenotypes found in patients with RD. MethodsMale 6-week-old BALB/c mice were randomly assigned to either active or inactive groups. Active groups were exercised by treadmill 1 hour a day for two weeks at a speed of 10m/min, meanwhile inactive groups were placed on static treadmills for the same duration. Light induced retinal degeneration (LIRD) was induced during the second week of exercise using light exposure of 5000 lux, control animals were kept at 50 lux. Retinal function was assessed using electroretinography (ERG) 5 days after LIRD. Retinas were collected 1-day and 5-days post-LIRD, sagittal sections were stained for inflammatory markers (GFAP and Iba1), TUNEL (cell death), and photoreceptor nuclei (outer nuclear layer; ONL) were quantified. RNA was extracted and miRNA expression quantified with GeneChip miRNA 4.0 array. ResultsActive+LIRD mice demonstrated significant preservation of retinal function, evidenced by higher a-wave and b-wave amplitudes in ERG 5-days post-LIRD, compared to inactive+LIRD mice. Retinal sections from active+LIRD mice had fewer Iba1+ cells and decreased GFAP labeling 5-days post-LIRD compared to inactive+LIRD mice. Active+LIRD mice had fewer ONL TUNEL+ cells compared to inactive+LIRD mice. Inactive+LIRD mice showed a decline in ONL counts 1-day post-LIRD with significant loss 5-days post-LIRD compared to active+LIRD mice. In active groups, exercise promoted significant differences in miRNA expression, such as miR-302b, miR-192-5p, miR-187 compared to inactive groups. ConclusionsOur results indicate that treadmill exercise preserved photoreceptor density, slowed and or prevented apoptosis in the ONL, and decreased the presence/recruitment of inflammatory cells in the neural retina. Altered miRNA expression profiles in active groups are associated with cell survival (miR-302b), oxidative stress regulation (miR-192-5p) and photoreceptor homeostasis (miR-187). These results reveal how exercise alters the retinal inflammatory response over the course of 1-day to 5-days, providing insight into exercise-based therapies and treatments for RD and neuroinflammatory diseases.

neuroscience↗

bioRxiv2021

Light-regulated SIK1 remodels the synaptic phosphoproteome to induce sleep

The sleep and circadian systems act in concert to regulate sleep-wake timing, yet the molecular mechanisms that underpin their interaction to induce sleep remain unknown. Synaptic protein phosphorylation, driven by the kinase SIK3, correlates with sleep pressure, however it is unclear whether these phosphoproteome changes are causally responsible for inducing sleep. Here we show that the light-dependent activity of SIK1 controls the phosphorylation of a subset of the brain phosphoproteome to induce sleep in a manner that is independent of sleep pressure. By uncoupling phosphorylation and sleep induction from sleep pressure, we establish that synaptic protein phosphorylation provides a causal mechanism for the induction of sleep under different environmental contexts. Furthermore, we propose a framework that details how the salt-inducible kinases regulate the synaptic phosphoproteome to integrate exogenous and endogenous stimuli, thereby providing the molecular basis upon which the sleep and circadian systems interact to control the sleep-wake cycle.

neuroscience↗

bioRxiv2021

α-lipoic acid has the potential to normalize copper metabolism, which is dysregulated in Alzheimer's disease

Alzheimers disease (AD) is an age-dependent progressive neurodegenerative disorder and the most common cause of dementia. The treatment and prevention of AD present immense yet unmet needs. One of the hallmarks of AD is the formation of extracellular amyloid plaques in the brain, composed of amyloid-beta (A{beta}) peptides. Multiple amyloid-targeting drug candidates have recently failed in clinical trials, which creates the necessity to focus also on alternative therapeutic strategies. One factor contributing to the development of AD is dysregulated copper metabolism, reflected in the intracellular copper deficit and excess extracellular copper levels. In the current study, we follow the widely accepted hypothesis that the normalization of copper metabolism leads to the prevention or slowing of the disease and searched for new copper-regulating ligands. We demonstrate that the natural intracellular copper chelator, -lipoic acid (LA) translocates copper from extracellular to intracellular space in a SH-SY5Y-based neuronal cell model, and is thus suitable to alleviate the intracellular copper deficit characteristic of AD neurons. Furthermore, we show that supplementation with LA protects the Drosophila melanogaster model of AD from developing AD phenotype, reflecting in decreased locomotor activity. Collectively, these results provide evidence that LA has the potential to normalize copper metabolism in AD and supports the hypothesis that LA supplementation may serve as a promising cost-effective method for the prevention and/or treatment of AD. Significance statementAlzheimers disease (AD) is a major biomedical concern that requires novel effective prevention and treatment approaches. An early determinant of AD pathology is dysregulated copper metabolism, which initiates the amyloid cascade, induces oxidative stress and impairs the functioning of cellular copper proteins, all contributing to the development of neurodegeneration. We suggest that the natural copper chelator -lipoic acid (LA) can normalize impaired copper metabolism in AD. We demonstrate that LA promotes the influx of copper into SH-SY5Y cells in a dose-dependent manner. Moreover, we show that LA alleviates the disease phenotype in a Drosophila melanogaster model of AD. Together with previously published data, these results support the hypothesis that LA has the potential for the prevention and treatment of AD.

neuroscience↗