Biology subjects

Guinovart, J. J.

Publications and source records attributed to Guinovart, J. J..

3 recordsLinked to original sources

bioRxiv2022

DISRUPTED CEREBRAL PERI-MICROVASCULAR GLYCOGEN PROMOTES CAPILLARY CONSTRICTIONS AND AGGRAVATES ISCHEMIA IN MICE

Ischemic stroke results in sudden blood flow cessation, thus, unmet energy requirements. Although the clotted artery can be recanalized and blood flow is restored, brain perfusion may not be fully attained due to microvascular constrictions. Under glucose deprived and hypoxic conditions, glucose derived from the glycogen stored around peri-microvascular astrocyte end-feet may serve as an emergency fuel to meet the metabolic demand during acute period of ischemic stroke. To elucidate the impact of glycogen utilization on brain microcirculation, we administered glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) intracerebroventricularly. Transgenic mice in which glycogen synthase-1 expression was selectively knocked out in central nervous system (GYS1Nestin-KO) were also used. Both approaches caused microvascular constrictions mediated by CD13-positive pericyte contractions. When mice with disrupted glycogen utilization were subjected to MCA ischemia, pericyte-mediated microvascular constrictions and the infarct volumes were further increased compared to untreated controls or wild type littermates. Perimicrovascular glycogen depletions were highly correlated with microvascular constrictions as shown by Periodic acid Schiff (PAS) staining and immunolabeling with anti-glycogen antibodies. Imaging of regional cortical blood flow changes during ischemia disclosed severely compromised blood flow dynamics in mice with disrupted glycogen metabolism. In conclusion, disrupting glycogen utilization causes ischemic-like microvascular constrictions under non-ischemic circumstances and increases susceptibility to brain ischemia. Understanding the role of glycogen at neurogliovascular level in brain may provide novel insight to the pathophysiology of ischemic stroke and therapeutic opportunities. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/505172v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1a4972borg.highwire.dtl.DTLVardef@c09847org.highwire.dtl.DTLVardef@4d961forg.highwire.dtl.DTLVardef@1bae0de_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Lack of p62 impairs glycogen aggregation and exacerbates pathology in a mouse model of myoclonic epilepsy of Lafora

BackgroundLafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates--the so-called Lafora Bodies (LBs)--in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. MethodsTo study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malinKO) lacking p62. ResultsDeletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. ConclusionsThese results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which to reduce the deleterious consequences of its accumulation in the brain.

neuroscience↗

bioRxiv2020

Lack of astrocytic glycogen alters synaptic plasticity but not seizure susceptibility

Brain glycogen is mainly stored in astrocytes. However, recent studies both in vitro and in vivo indicate that glycogen also plays important roles in neurons. By conditional deletion of glycogen synthase (GYS1), we previously developed a mouse model entirely devoid of glycogen in the central nervous system (GYS1Nestin-KO). These mice displayed altered electrophysiological properties in the hippocampus and increased susceptibility to kainate-induced seizures. To understand which of these functions is related to astrocytic glycogen, in the present study we generated a mouse model in which glycogen synthesis is eliminated specifically in astrocytes (GYS1Gfap-KO). Electrophysiological recordings of awake behaving mice revealed alterations in input/output curves and impaired long-term potentiation, similar, but to a lesser extent, to those obtained with GYS1Nestin-KO mice. Surprisingly, GYS1Gfap-KO mice displayed no change in susceptibility to kainate-induced seizures as determined by fEPSP recordings and video monitoring. These results confirm the importance of astrocytic glycogen in synaptic plasticity.

biochemistry↗