Biology subjects

Melov, S.

Publications and source records attributed to Melov, S..

3 recordsLinked to original sources

bioRxiv2023

Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington's Disease and Possible Therapeutic Avenues

Huntingtons disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the HTT gene, ultimately resulting in the generation of a mutant HTT (mHTT) protein. Although mHTT is expressed in various tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and the subsequent motor function impairment in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment has an important role. To explore the effects of mHTT on MSN development, we differentiated HD induced pluripotent stem cells (iPSC) and isogenic controls into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and mature MSNs. Single-cell RNA sequencing revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of fetal striatal neurons. However, in the HD MSN cultures, the differentiation process downregulated several crucial genes required for proper MSN maturation, including Achaete-scute homolog 1 and members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as the MSNs matured, including the NRF2-mediated oxidative stress response and mitogen-activated protein kinase signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce the opposite gene expression pattern. Our analysis pinpointed numerous small molecules with known benefits in HD models, as well as previously untested novel molecules. A top novel candidate, Cerulenin, partially restored the DARPP-32 levels and electrical activity in HD MSNs, and also modulated genes involved in multiple HD-related pathways.

neuroscience↗

bioRxiv2023

A Single Cell Time Course of Senescence Uncovers Discrete Cell Trajectories and Transcriptional Heterogeneity

Senescent cells (SnCs) are typically studied as endpoints of a complex transformational process, owing to their frequent maladaptive effects on surrounding tissue and cells. SnCs accumulate with age, and while they ultimately comprise a small percentage of cells in tissues, they have important roles in age associated pathologies. Several obstacles remain in understanding the heterogeneous nature of senescence, and formulating potent beneficial intervention strategies. One approach targets senescent cells and kills them ("senolytic" approach), and is often driven by a low resolution understanding of SnC identity, which risks both incomplete clearance and off-target effects. Cellular senescence is not a singular binary response, but a suite of response trajectories that vary by multiple parameters including inducer and initial cell state. In order to elucidate the developmental trajectories of SnCs, we performed single-cell RNA sequencing on IMR90 lung fibroblasts senescencing across a 12 day time period. Our analysis reveals substantial heterogeneity in gene expression within timepoints and across the full time-course. We uncovered unique markers and differentially regulated pathways in cell populations within each timepoint. Supervised trajectory inference of the time-course data uncovered the root-origin and fates of distinct SnC lineages over 3 stages of senescence induction. Altogether our data provide a novel approach to stud SnC development, identifying cell states of interest, and differentiating between SnCs and quiescent cells. This will aid in identifying key targets for therapeutic intervention in senescence.

cell biology↗

bioRxiv2021

Dietary restriction and clock delay eye aging to extend lifespan in D. melanogaster

Many vital processes in the eye are under circadian regulation, and circadian dysfunction has emerged as a potential driver of eye aging. Dietary restriction is one of the most robust lifespan-extending therapies and amplifies circadian rhythms with age. Herein, we demonstrate that dietary restriction extends lifespan in D. melanogaster by promoting circadian homoeostatic processes that protect the visual system from age- and light- associated damage. Disrupting circadian rhythms in the eye by inhibiting the transcription factor, Clock (CLK), or CLK-output genes, accelerated visual senescence, induced a systemic immune response, and shortened lifespan. Flies subjected to dietary restriction were protected from the lifespan-shortening effects of photoreceptor activation. Inversely, photoreceptor inactivation, achieved via mutating rhodopsin or housing flies in constant darkness, primarily extended lifespan in flies reared on a high-nutrient diet. Our findings establish the eye as a diet-sensitive modulator of lifespan and indicate that vision is an antagonistically pleiotropic process that contributes to organismal aging.

neuroscience↗