Biology subjects

Farinas, A.

Publications and source records attributed to Farinas, A..

4 recordsLinked to original sources

bioRxiv2025

Spatial and molecular insights into microglial roles in cerebellar aging

Aging induces region-specific functional decline across the brain. The cerebellum, critical for motor coordination and cognitive function, undergoes significant structural and functional changes with age. The molecular mechanisms driving cerebellar aging--particularly the role of cerebellar glia, including microglia--remain poorly understood. Here, we used single-nuclei RNA sequencing (snRNA-seq), microglial bulk RNA-seq, and multiplexed error-robust fluorescence in situ hybridization (MERFISH) to characterize transcriptional changes associated with cellular aging in the mouse cerebellum. We discovered that microglia exhibited the most pronounced age-related changes of all cell types and that their transcriptional signatures pointed to enhanced neuroprotective immune activation and reduced lipid-droplet accumulation compared to hippocampal microglia. Furthermore, cerebellar microglia in aged mice, compared to young mice, were found in closer proximity to granule cells. This relationship was characterized using the newly defined neuron-associated microglia score, which captures proximity-dependent transcriptional changes and suggests a novel microglial responsiveness. These findings underscore the unique adaptations of the cerebellum during aging and its potential resilience to Alzheimers disease (AD) related pathology, providing crucial insight into region-specific mechanisms that may shape disease susceptibility.

neuroscience↗

bioRxiv2024

Synapse protein signatures in cerebrospinal fluid and plasma predict cognitive maintenance versus decline in Alzheimers disease

Rates of cognitive decline in Alzheimers disease (AD) are extremely heterogeneous, with ages of symptom onset ranging from age 40-100 years and conversion from mild cognitive impairment to AD dementia taking 2-20 years. Development of biomarkers for amyloid-beta (A{beta}) and tau protein aggregates, the hallmark pathologies of AD, have improved patient monitoring/stratification and drug development, but they still only explain 20-40% of the variance in cognitive impairment (CI) in AD. To discover additional molecular drivers and biomarkers of AD dementia, we perform cerebrospinal fluid (CSF) proteomics on 3,416 individuals from six deeply phenotyped prospective AD case-control cohorts. We identify synapse proteins as the strongest correlates of CI, independent of A{beta} and tau. Using machine learning we derive the CSF YWHAG:NPTX2 synapse protein ratio, a robust correlate of CI, which explains 27% of the variance in CI beyond CSF PTau181:A{beta}42, 10% beyond tau PET, and 50% beyond CSF NfL in A{beta} positive individuals. We find YWHAG:NPTX2 also increases with normal aging as early as age 20 and increases at a faster rate in APOE4 carriers and autosomal dominant-AD mutation carriers. Most notably, YWHAG:NPTX2+ individuals (top 25th percentile) are 15-times (HR=15.4 [10.6-22.2]) more likely to experience cognitive decline over 15 years compared to YWHAG:NPTX2- individuals (bottom 25th percentile), and this rises to 19-times (HR=18.9 [10.83-32.9]) with additional stratification by A{beta} and phosphorylated tau status. Lastly, we perform plasma proteomics on 4,245 individuals to develop a plasma-based signature of CI which partly recapitulates CSF YWHAG:NPTX2. Overall, our findings underscore CSF YWHAG:NPTX2 and the corresponding plasma signature as robust prognostic biomarkers for AD onset and progression beyond gold-standard biomarkers of A{beta}, tau, and neurodegeneration and implicate synapse dysfunction as a core driver of AD dementia.

neuroscience↗

bioRxiv2023

Glia detect and mount a protective response to loss of dendrite substructure integrity in C. elegans

Neurons have elaborate structures that determine their connectivity and functions. Changes in neuronal structure accompany learning and memory formation and are hallmarks of neurological disease. Here we show that glia monitor dendrite structure and respond to dendrite perturbation. In C. elegans mutants with defective sensory-organ dendrite cilia, adjacent glia accumulate extracellular matrix-laden vesicles, secrete excess matrix around cilia, alter gene expression, and change their secreted protein repertoire. Inducible cilia disruption reveals that this response is acute. DGS-1, a 7-transmembrane domain neuronal protein, and FIG-1, a multifunctional thrombospondin-domain glial protein, are required for glial detection of cilia integrity, and exhibit mutually-dependent localization to and around cilia, respectively. While inhibiting glial secretion disrupts dendritic cilia properties, hyperactivating the glial response protects against dendrite damage. Our studies uncover a homeostatic protective dendrite-glia interaction and suggest that similar signaling occurs at other sensory structures and at synapses, which resemble sensory organs in architecture and molecules.

neuroscience↗

bioRxiv2022

Cell non-autonomous control of autophagy and metabolism by glial cells

Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.

neuroscience↗