Biology subjects

Fernandez-Chacon, R.

Publications and source records attributed to Fernandez-Chacon, R..

3 recordsLinked to original sources

bioRxiv2026

Microglia Rank signaling regulates GnRH function and the Hypothalamic-Pituitary-Gonadal axis

The hypothalamic-pituitary-gonadal axis (HPG) controls pubertal development, sexual maturation, and fertility. We hereby demonstrate a new role of hypothalamic microglia in controlling the HPG axis through Rank signaling, a pathway known for its role in bone and mammary gland biology. Whole-body and microglia Rank depletion leads to hypogonadotropic hypogonadism (HH) resulting from an alteration in gonadotropin-releasing hormone (GnRH) function. In addition, we identify rare gene variants of RANK in patients with HH. Transcriptional profiling upon pubertal Rank loss reveals defective microglia activation and morphological alterations in the median eminence (ME), decreasing the contacts and engulfment of GnRH terminal projections and impairing GnRH responses to kisspeptin. Overall, our data uncovers the crucial role of microglia in regulating GnRH function through Rank signaling, with implications for reproductive maturation and fertility. One-Sentence SummaryMicroglia regulates GnRH function through RANK signaling

cell biology↗

bioRxiv2025

Allosteric modulation of TIA-1 phase separation by double serine phosphorylation

In response to diverse harmful stimuli, eukaryotic cells generate cytoplasmic stress granules (SGs), mainly composed of mRNAs and RNA-binding proteins (RBPs). RBPs are fine-tuned by a diverse array of post-translational modifications (PTMs), with important consequences for the assembly, dynamics and clearance of SGs. One of the best characterized SG nucleators is the RBP T-cell intracellular antigen 1 (TIA-1), although knowledge about the structural and functional impact of its identified PTMs is very limited. TIA-1 is organized into three RNA-recognition motifs (RRMs) and a C-terminal prion-related domain (PRD) that drives its phase separation from the cytosol. Here, we analyzed the effect of TIA-1 double phosphorylation in RRM3, at serines 198 and 199. Microscopic observations revealed an increased propensity of the phosphomimetic TIA-1 S198/199E to undergo liquid-liquid phase separation (LLPS) and self-assemble into SGs independently of stress stimuli. Our computational simulations, supported by NMR data, have suggested that such phosphorylations promote the formation of a {beta}-hairpin motif at the beginning of the PRD. Moreover, the ALS-associated mutation V283M in TIA-1 was predicted to lead to the formation of an aberrant structure in the {beta}-hairpin region, highlighting the fine balance between physiological and pathogenic TIA-1 phase transition, and the importance of a better understanding of the molecular mechanisms underlying the liquid demixing of this RBP.

biophysics↗

bioRxiv2023

Neuronal lipofuscinosis caused by Kufs disease/CLN4 DNAJC5 mutations but not by a CSPα/DNAJC5 deficiency

Kufs disease/CLN4 is an autosomal dominant neurodegenerative disorder that affects young adults, caused by mutations in the DNAJC5 gene that encodes the synaptic vesicle co-chaperone Cysteine String Protein (CSP/DNAJC5). The Leu115Arg and Leu116{Delta} mutations in humans are known to independently cause the disease, although the underlying mechanisms are unknown. To investigate the disease mechanisms in vivo, we generated three independent mouse lines overexpressing different versions of CSP/DNAJC5 under the neuron-specific Thy1 promoter: wild-type (WT), Leu115Arg, and Leu116{Delta}. Mice expressing mutant CSP/DNAJC5 are viable and do not show any significant increase in morbidity or mortality. However, we observed the presence of pathological lipofuscinosis in the mutants, indicated by autofluorescent punctate structures labeled with antibodies against ATP synthase subunit C, which were absent in the WT transgenic line. Additionally, transmission electron microscopy revealed intracellular structures resembling granular osmiophilic deposits (GRODs), observed in Kufs disease patients, in the mutants but not in non-transgenic controls or the WT transgenic mice. Notably, conventional, or conditional knockout mice lacking CSP/DNAJC5 did not exhibit any signs of increased lipofuscinosis or GRODs. Our novel mouse models thus provide a valuable tool to investigate the molecular mechanisms underlying Kufs disease/CLN4. We conclude that DNAJC5 mutations cause neuronal lipofuscinosis through a cell-autonomous gain of a novel but pathological function of CSP/DNAJC5.

neuroscience↗