Biology subjects

Hernandez-Diaz, S.

Publications and source records attributed to Hernandez-Diaz, S..

4 recordsLinked to original sources

bioRxiv2026

The autophagy core protein Atg18 regulates exosome release and rescues pathogenic dysfunction associated to Parkinson Sac domain mutation in Synaptojanin

Macroautophagy, a catabolic process conserved across evolution, participates in fundamental aspects of synaptic function and neuronal survival. Exosomes are extracellular vesicles that mediate cell communication, including emerging roles mediating brain intercellular signaling, synaptic function and neuronal survival. Indeed, both autophagy and exosome release interact with each other, but this interplay is poorly characterized at the neuronal synapse, especially in the context of neurodegenerative diseases. Here, we report that at the presynaptic compartment the autophagy protein Atg18a/WIPI2 regulates exosome release at the level of the multivesicular body. The Parkinson disease mutation R258Q in the protein Synaptojanin inhibits synaptic autophagy, and causes locomotion deficits, seizures and neurodegeneration. We found that this mutation also reduces exosome release and that the dopaminergic overexpression of Atg18a in Synaptojanin mutant animals restores exosome release, locomotion and dopaminergic survival without restoring synaptic autophagy. Our data reports a novel function of Atg18a in the regulation of exosome release and spotlights the role of exosome release in the pathogenesis of Parkinson disease.

neuroscience↗

bioRxiv2023

Synaptogyrin regulates neuronal activity dependent autophagy to degrade synaptic vesicle components and pathological Tau

Synapses are specialized neuronal compartments essential for brain communication. Neuronal communication mostly relies on the adequate supply and renovation of synaptic vesicles that fuse with the plasma membrane and release neurotransmitters in response to action potentials. Autophagy is an evolutionary conserved cellular mechanism essential for homeostasis that can be locally regulated in the neuronal synapse. However, the precise mechanisms controlling synaptic autophagy, especially during neuronal communication and pathological scenarios, remain elusive. Here, we report that neuronal activity and amino-acid deprivation regulate synaptic autophagy via distinct molecular mechanisms. We show that Synaptogyrin, a highly abundant presynaptic protein found in synaptic vesicles, is a novel negative regulator of synaptic autophagy in response to neuronal activity without affecting autophagy induction via amino-acid deprivation. We demonstrate that loss of Synaptogyrin modifies the localization of the autophagy protein Atg9 and boosts autophagosome formation at the synapse. Furthermore, activation of synaptic autophagy by loss of Synaptogyrin, but not by amino-acid deprivation, leads to the degradation of synaptic vesicle components via autophagy. Reducing the levels of Synaptogyrin results in the degradation of synaptic Tau via autophagy and restores autophagy dysfunction observed in a Drosophila Tau model of Frontotemporal Dementia (FTD). Our data provide novel and valuable information to understand how autophagy is regulated at the synapse in response to neuronal activity and how this process participates in neuronal (dys)function.

neuroscience↗

bioRxiv2019

Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth

BackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.\n\nMethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.\n\nResults6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: -1.3 [-2.3 to -0.3]); were 0.1 standard deviations (SDs) lighter (-0.1 [-0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (-0.2 [-0.3 to -0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (1.1 [-3.0 to 0.8]); were 0.1 SDs lighter (-0.1 [-0.3 to 0.0]); and had the same head circumference. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (-0.5 [-2.6 to 1.6]); were 0. 1 SDs lighter (-0.1 [-0.3 to 0.0]); and were 0.1 SDs smaller (-0.1 [-0.3 to 0.1]) in head circumference. Valproic acid-exposed infants had, on average, the same duration of gestation and birth weight z-score, but were 0.2 SDs smaller (-0.2 [-0.2 to -0.1]) in head circumference. More negative associations at the left tail of pregnancy duration and birth weight z-score, effect-measure modification, and dose-response relations were noted for some of the associations. Observed associations were generally of smaller magnitude than that of smoking, assessed as a potential confounder in the same models.\n\nConclusionsIn comparison with lamotrigine, valproic acid and carbamazepine had a more negative association with head circumference than other study AEDs.

epidemiology↗

bioRxiv2018

The distribution of antibiotic use and its association with antibiotic resistance

Antibiotic use is a primary driver of antibiotic resistance. However, antibiotic use can be distributed in different ways in a population, and the association between the distribution of use and antibiotic resistance has not been explored. Here we tested the hypothesis that repeated use of antibiotics has a stronger association with population-wide antibiotic resistance than broadly- distributed, low-intensity use. First, we characterized the distribution of outpatient antibiotic use across US states, finding that antibiotic use is uneven and that repeated use of antibiotics makes up a minority of antibiotic use. Second, we compared antibiotic use with resistance for 72 pathogen-antibiotic combinations across states. Finally, having partitioned total use into extensive and intensive margins, we found that intense use had a weaker association with resistance than extensive use. If the use-resistance relationship is causal, these results suggest that reducing total use and selection intensity will require reducing broadly-distributed, low- intensity use.

epidemiology↗