Biology subjects

Frakes, A. E.

Publications and source records attributed to Frakes, A. E..

5 recordsLinked to original sources

bioRxiv2025

A FMRF-amide peptide that regulates cell non-autonomous protein homeostasis in C. elegans.

The coordination of protein homeostasis from the brain to periphery is essential for the health and survival of all animals. In C. elegans, glia serve a central role in coordinating organismal protein homeostasis and longevity via the unfolded protein response of the endoplasmic reticulum (UPRER). However, the full extent of the cell non-autonomous response and the identity of the signaling molecules required remained unknown. Here, we show that glial UPRER activation induces robust transcriptomic changes in specific tissue types across the animal, particularly in pathways related to neuropeptide signaling. We performed neuropeptidomics and loss and gain-of-function genetic screens and identified a single neuropeptide, FLP-17, that is sufficient but not necessary to induce cell non-autonomous activation of the UPRER. FLP-17 is sufficient to protect against chronic ER stress and age-dependent protein aggregation. We determined that FLP-17 acts through the receptor, EGL-6, to activate cell non-autonomous UPRER. This work reveals a complex peptidergic signaling network initiated by glial activation of the UPRER to regulate organismal protein homeostasis.

neuroscience↗

bioRxiv2025

Parental origin of transgene determines recombination efficiency in GFAP-creERT2 mice

The Cre-loxP system is a powerful tool for spatial and temporal genetic manipulations. However, the system is prone to several limitations and caveats with respect to variable expression and recombination in unintended cell types. Using one of the most widely used astrocyte Cre lines, hGFAP-creERT2 (GFAP-cre/ERT2)505Fmv/J), we found that parental origin of the hGFAP-creERT2 transgene is a determinant of recombination efficiency. Recombination was robust in animals with paternally inherited hGFAP-creERT2. However, animals with maternally inherited Cre exhibited little to no recombination. This result was recapitulated using female hGFAP-creERT2 mice procured directly from Jackson Laboratory. We did not observe transgenerational suppression of Cre recombination in maternally inherited hGFAP-CreERT2. These data highlight the need for careful planning and documentation of breeding schemes when working with Cre mice.

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↗

bioRxiv2022

Glia of C. elegans coordinate the heat shock response independent of the neuronal thermosensory circuit and serotonin

As organisms age, they lose the ability to induce appropriate stress responses, becoming vulnerable to protein toxicity and tissue damage. Neurons can signal to peripheral tissues to induce protective organelle-specific stress responses. Recent work has demonstrated a novel and independent role of glia in inducing such responses. Here, we show that overexpression of heat shock factor 1 (hsf-1) in the four astrocyte-like cephalic sheath cells of C. elegans is sufficient to induce a non-cell autonomous cytosolic unfolded protein response (UPR), also known as the heat shock response (HSR), in distal cells. These animals upregulate the HSR in peripheral cells and have increased lifespan and resistance to heat stress. This glial HSR regulation is independent of the canonical neuronal thermosensory circuit and of known neurotransmitters but is dependent on the small clear vesicle release protein UNC-13. Additionally, HSF-1 and the FOXO transcription factor DAF-16 are partially required in peripheral tissues for increase of non-autonomous HSR, lifespan, and thermotolerance. We find that cephalic sheath glial hsf-1 over-expression leads to increased pathogen resistance, which suggests a role for this signaling pathway in immune function.

neuroscience↗

bioRxiv2021

Aging alters the metabolic flux signature of the ER unfolded protein response in vivo in mice

Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared to young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, only a significant reduction was seen in the triglyceride fraction. These data indicate that aged mice have an exaggerated response to ER stress, which may indicate that the aging renders the UPRER less effective in resolving proteotoxic stress.

physiology↗