Biology subjects

Huntington, T. E.

Publications and source records attributed to Huntington, T. E..

4 recordsLinked to original sources

bioRxiv2021

Aging reduces calreticulin expression and alters spontaneous calcium signals in astrocytic endfeet of the mouse dorsolateral striatum

Aging-related impairment of the blood brain barrier (BBB) and neurovascular unit (NVU) increases risk for neurodegeneration. Among the various cells participating in BBB and NVU function, spontaneous Ca2+ signals in astrocytic endfeet are crucial for maintaining BBB and NVU integrity. To assess if aging is associated with changes in spontaneous Ca2+ signals within astrocytic endfeet of the dorsolateral striatum (DLS), we expressed a genetically encoded Ca2+ indicator, Lck-GCaMP6f in DLS astrocytes of young (3-4 month) and aging (20-24 month) mice. Compared to young mice, endfeet in the DLS of aging mice demonstrated a decrease in calreticulin (CALR) expression, and dramatic alterations in the dynamics of endfoot membrane-associated and mitochondrial Ca2+ signals. While young mice required both extracellular and endoplasmic reticulum (ER) Ca2+ sources for generating endfoot Ca2+ signals, aging mice showed exclusive dependence on ER Ca2+. These data suggest that aging is associated with significant changes in Ca2+ buffers and Ca2+ signals within astrocytic endfeet, which has important implications for understanding mechanisms involved in aging-related impairment of the BBB and NVU. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/461710v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d61571org.highwire.dtl.DTLVardef@19e2f9org.highwire.dtl.DTLVardef@18455cborg.highwire.dtl.DTLVardef@11ca928_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAging mice show reduced calreticulin expression in astrocytic endfeet C_LIO_LIAging astrocytic endfeet show dramatic changes in spontaneous Ca2+ activity C_LIO_LICa2+ signals in aging endfeet depend exclusively on endoplasmic reticulum Ca2+ C_LI

neuroscience↗

bioRxiv2021

The Age-Dependent Decline in Neuron Growth Potential in the CNS is Associated with an Age-Related Dysfunction of Neuronal Mitochondria

The age of incidence of Spinal Cord Injury (SCI) and the average age of people living with SCI is continuously increasing. In contrast, SCI is extensively modelled in young adult animals, hampering translation of research to clinical application. While there has been significant progress in manipulating axon growth after injury, how it is impacted by aging impacts this is still unknown. Aging is associated with a decline in mitochondrial functions, whereas mitochondria are essential to successful neurite and axon growth. Using isolation and culture of adult cortical neurons, we have analyzed mitochondrial changes in 2-, 6-, 12- and 18-month mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest dysfunctional mitochondria in older neurons are involved in the age-dependent reduction in neuron growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can compound one another to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.

neuroscience↗

bioRxiv2020

In situ characterization of calcium fluxes in astrocytic mitochondria from the mouse striatum and hippocampus

Astrocytes govern critical aspects of brain function via Ca2+ signals, the majority of which associate with mitochondria. However, little is known with regard to in situ sources, kinetics or mechanisms of Ca2+ influx in astrocytic mitochondria. To address this knowledge gap, we expressed the genetically encoded calcium indicator, GCaMP6f within the mitochondrial matrix of adult mouse astrocytes in the dorsolateral striatum (DLS) and hippocampus (HPC). We found spontaneous Ca2+ events in astrocytic mitochondria with subcellular differences between somatic, branch, and branchlet mitochondria, as well as inter-regional differences between astrocytes in the DLS and HPC. We also found a strong dependency of spontaneous mitochondrial Ca2+ fluxes on endoplasmic reticulum stores, the surprising lack of a major role for the mitochondrial calcium uniporter, MCU, and dual mitochondrial Ca2+ responses with multiple neurotransmitter agonists. Together, our findings provide a foundational understanding of mechanisms for Ca2+ influx in astrocytic mitochondria within disease-relevant brain regions.

neuroscience↗

bioRxiv2019

LRRK2 regulates innate immune responses and neuroinflammation during Mycobacterium tuberculosis infection

Despite many connections between mutations in leucine-rich repeat kinase 2 (LRRK2) and susceptibility to mycobacterial infection, we know little about its function outside of the brain, where it is studied in the context of Parkinsons Disease (PD). Here, we report that LRRK2 controls peripheral macrophages and brain-resident glial cells ability to respond to and express inflammatory molecules. LRRK2 KO macrophages express elevated basal levels of type I interferons, resulting from defective purine metabolism, mitochondrial damage, and engagement of mitochondrial DNA with the cGAS DNA sensing pathway. While LRRK2 KO mice can control Mycobacterium tuberculosis (Mtb) infection, they exhibit exacerbated lung inflammation and altered activation of glial cells in PD-relevant regions of the brain. These results directly implicate LRRK2 in peripheral immunity and support the \"multiple-hit hypothesis\" of neurodegenerative disease, whereby infection coupled with genetic defects in LRRK2 create an immune milieu that alters activation of glial cells and may trigger PD.

immunology↗