Dataset Information

Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

ABSTRACT:

Background

In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression.

Objective

The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes.

Methods

Primary adult astrocytes were derived from two HD mouse models; the fast-progressing R6/2 and slower progressing Q175. With the use of laser nanosurgery, a single astrocyte was lysed within an astrocyte network. The phagocytic response of astrocytes was observed with phase contrast and by fluorescence microscopy for GFP-LC3 transiently transfected cells.

Results

Astrocyte phagocytosis was significantly diminished in primary astrocytes, consistent with the progression of HD in R6/2 and Q175 mouse models. This was defined by the number of astrocytes responding via phagocytosis and by the average number of vesicles formed per cell. GFP-LC3 was found to increasingly localize to phagocytic vesicles over a 20-min imaging period, but not in HD mice, suggesting the involvement of LC3 in astrocyte phagocytosis.

Conclusion

We demonstrate a progressive decrease in LC3-associated phagocytosis in HD mouse striatal astrocytes.

SUBMITTER: Wakida NM

PROVIDER: S-EPMC9028675 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

Wakida Nicole M NM Lau Alice L AL Nguyen Jessica J Cruz Gladys Mae S GMS Fote Gianna M GM Steffan Joan S JS Thompson Leslie M LM Berns Michael W MW

Journal of Huntington's disease 20220101 1

<h4>Background</h4>In recent years the functions of astrocytes have shifted from conventional supportive roles to also include active roles in altering synapses and engulfment of cellular debris. Recent studies have implicated astrocytes in both protective and pathogenic roles impacting Huntington's disease (HD) progression.<h4>Objective</h4>The goal of this study is to determine if phagocytosis of cellular debris is compromised in HD striatal astrocytes.<h4>Methods</h4>Primary adult astrocytes ...[more]

PMID: 35253772

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Project description:BackgroundRecent findings suggest that individuals with Huntington's disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear.ObjectivesTo evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments.MethodsTwenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment.ResultsCompared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P < 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P < 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test-retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls.ConclusionsIndividuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls.

Project description:IntroductionHuntington's disease (HD) is a neurodegenerative disease that primarily affects the striatum, a brain region that controls movement and some forms of cognition. Neuronal dysfunction and loss in HD is accompanied by increased astrocyte density and astrocyte pathology. Astrocytes are a heterogeneous population classified into multiple subtypes depending on the expression of different gene markers. Studying whether mutant Huntingtin (HTT) alters specific subtypes of astrocytes is necessary to understand their relative contribution to HD.MethodsHere, we studied whether astrocytes expressing two different markers; glial fibrillary acidic protein (GFAP), associated with astrocyte activation, and S100 calcium-binding protein B (S100B), a marker of matured astrocytes and inflammation, were differentially altered in HD.ResultsFirst, we found three distinct populations in the striatum of WT and symptomatic zQ175 mice: GFAP+, S100B+, and dual GFAP+S100B+. The number of GFAP+ and S100B+ astrocytes throughout the striatum was increased in HD mice compared to WT, coinciding with an increase in HTT aggregation. Overlap between GFAP and S100B staining was expected, but dual GFAP+S100B+ astrocytes only accounted for less than 10% of all tested astrocytes and the number of GFAP+S100B+ astrocytes did not differ between WT and HD, suggesting that GFAP+ astrocytes and S100B+ astrocytes are distinct types of astrocytes. Interestingly, a spatial characterization of these astrocyte subtypes in HD mice showed that while S100B+ were homogeneously distributed throughout the striatum, GFAP+ preferentially accumulated in "patches" in the dorsomedial (dm) striatum, a region associated with goal-directed behaviors. In addition, GFAP+ astrocytes in the dm striatum of zQ175 mice showed increased clustering and association with white matter fascicles and were preferentially located in areas with low HTT aggregate load.DiscussionIn summary, we showed that GFAP+ and S100B+ astrocyte subtypes are distinctly affected in HD and exist in distinct spatial arrangements that may offer new insights to the function of these specific astrocytes subtypes and their potential implications in HD pathology.

Dataset Information

Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

Background

Objective

Methods

Results

Conclusion

Publications

Diminished LC3-Associated Phagocytosis by Huntington's Disease Striatal Astrocytes.

Similar Datasets

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