Inducible knockout of 
      <i>Clec16a</i> in mice results in sensory neurodegeneration

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16a ^ΔUBC mice, to investigate the loss of function of CLEC16A. The mice exhibited a neuronal phenotype including tremors and impaired gait that rapidly progressed to dystonic postures. Nerve conduction studies and pathological analysis revealed loss of sensory axons that are associated with this phenotype. Activated microglia and astrocytes were found in regions of the CNS. Several mitochondrial-related proteins were up- or down-regulated. Upregulation of interferon stimulated gene 15 (IGS15) were observed in neuronal tissues. CLEC16A expression inversely related to IGS15 expression. ISG15 may be the link between CLEC16A and downstream autoimmune, inflammatory processes. Our results demonstrate that a whole-body, inducible knockout of Clec16a in mice results in an inflammatory neurodegenerative phenotype resembling spinocerebellar ataxia.

Related collections

Most cited references 72

Record: found
Abstract: found
Article: not found

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.

Taichi Hara, Kenji Nakamura, Makoto Matsui … (2006)

Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.

0 comments Cited 426 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

GFAP in health and disease.

J Middeldorp, E M Hol (2011)

Glial fibrillary acidic protein (GFAP) is the main intermediate filament protein in mature astrocytes, but also an important component of the cytoskeleton in astrocytes during development. Major recent developments in astrocyte biology and the discovery of novel intermediate filament functions enticed the interest in the function of GFAP. The discovery of various GFAP splice variants gave an additional boost to explore this protein in more detail. The structural role of GFAP in astrocytes has been widely accepted for a long time, but over the years, GFAP has been shown to be involved in astrocyte functions, which are important during regeneration, synaptic plasticity and reactive gliosis. Moreover, different subpopulations of astrocytes have been identified, which are likely to have distinctive tasks in brain physiology and pathology, and which are not only classified by their spatial and temporal appearance, but also by their specific expression of intermediate filaments, including distinct GFAP isoforms. The presence of these isoforms enhances the complexity of the astrocyte cytoskeleton and is likely to underlie subtype specific functions. In this review we discuss the versatility of the GFAP cytoskeletal network from gene to function with a focus on astrocytes during human brain development, aging and disease. Copyright © 2011 Elsevier Ltd. All rights reserved.

0 comments Cited 327 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Systemic inflammation and microglial activation: systematic review of animal experiments

Inge Hoogland, Carin Houbolt, David van Westerloo … (2015)

Background Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain. Methods We searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions. Results Fifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) messenger ribonucleic acid (mRNA) expression or protein levels. Interpretation Animal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria.

0 comments Cited 311 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Heather S. Hain: hainh@email.chop.edu

Hakon Hakonarson: hakonarson@email.chop.edu

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2045-2322

Publication date (Electronic): 29 April 2021

Publication date PMC-release: 29 April 2021

Publication date Collection: 2021

Volume: 11

Electronic Location Identifier: 9319

Affiliations

[1 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, The Center for Applied Genomics, , Children’s Hospital of Philadelphia, ; Philadelphia, PA 19104 USA

[2 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Neurology, The Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA 19104 USA

[3 ]GRID grid.239552.a, ISNI 0000 0001 0680 8770, Department of Neurology, , Children’s Hospital of Philadelphia, ; Philadelphia, PA 19104 USA

[4 ]GRID grid.25879.31, ISNI 0000 0004 1936 8972, Department of Pediatrics, The Perelman School of Medicine, , University of Pennsylvania, ; Philadelphia, PA 19104 USA

Article

Publisher ID: 88895

DOI: 10.1038/s41598-021-88895-0

PMC ID: 8084945

PubMed ID: 33927318

SO-VID: b53bec0e-1aba-4b27-80f8-378fc8ac67d2

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 14 January 2020

Date accepted : 30 March 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100006458, Children's Hospital of Philadelphia;

Award ID: Institute Development Award, endowed chair in genomic research

Award Recipient : Steven S. Scherer

Custom metadata

ScienceOpen disciplines: Uncategorized

Keywords: neurodegeneration,inflammation,genetics,immunology,neuroscience,neurology

Data availability:

ScienceOpen disciplines: Uncategorized

Keywords: neurodegeneration, inflammation, genetics, immunology, neuroscience, neurology

Inducible knockout of Clec16a in mice results in sensory neurodegeneration

Read this article at

Abstract

Related collections

Karger: Neurology and Neuroscience

Most cited references 72

Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.

GFAP in health and disease.

Systemic inflammation and microglial activation: systematic review of animal experiments

Author and article information

Contributors

Journal

Affiliations

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 393

Cited by 7

Most referenced authors 883