Inducible knockout of Clec16a in mice results in sensory neurodegeneration

Hain, Heather S.; Pandey, Rahul; Bakay, Marina; Strenkowski, Bryan; Harrington, D. E.; Romer, Micah; Motley, William W.; Li, Jian; Lancaster, Eunjoo; Roth, Lindsay M; Grinspan, Judith B.; Scherer, Steven S.; Hákonarson, Hákon

doi:10.1038/s41598-021-88895-0

Cited by 7 publications

(11 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A global knockout of CLEC16A in mice leads to abnormal mitophagy, upregulated inflammatory cytokine response, and increased risk of autoimmunity [12]. Interestingly, the knockout mice also develop severe neurological phenotypes with impaired gait and dystonic postures [13]. This is consistent with previous observations in two other mouse strains carrying independent constitutive CLEC16A mutations [14].…”

Section: Introductionsupporting

confidence: 89%

CLEC16A—An Emerging Master Regulator of Autoimmunity and Neurodegeneration

Pandey

Bakay

Hákonarson

2023

IJMS

Self Cite

View full text Add to dashboard Cite

CLEC16A is emerging as an important genetic risk factor for several autoimmune disorders and for Parkinson disease (PD), opening new avenues for translational research and therapeutic devel-opment. While the exact role of CLEC16A in health and disease is still being elucidated, the gene plays a critical role in the regulation of autophagy, mitophagy, endocytosis, intracellular trafficking, immune function, and in biological processes such as insulin secretion and others that are important to cellular homeostasis. As shown in both human and animal modeling studies, CLEC16A hypo-function predisposes to both autoinflammatory phenotype and neurodegeneration. While the two are clearly related, further functional studies are needed to fully understand the mechanisms in-volved for optimized therapeutic interventions. Based on recent data, mitophagy-inducing drugs may be warranted, and such therapy should be tested in clinical trials as these drugs would tackle the underlying pathogenic mechanism (s) and could treat or prevent symptoms of autoimmunity and neurodegeneration in individuals with CLEC16A risk variants. Accordingly, interventions di-rected at reversing the dysregulated mitophagy and the consequences of loss of function of CLEC16A without activating other detrimental cellular pathways could present an effective ther-apy. This review presents the emerging role of CLEC16A in health and disease and provides an update on the disease processes that are attributed to variants located in the CLEC16A gene, which are responsible for autoimmune disorders and neurodegeneration with emphasis on how this in-formation is being translated into practical and effective applications in the clinic.

show abstract

Section: Introductionsupporting

confidence: 89%

CLEC16A—An Emerging Master Regulator of Autoimmunity and Neurodegeneration

Pandey

Bakay

Hákonarson

2023

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Therefore, cellular changes in clec16a crispants were assessed despite their normal brain size. Several studies have shown the involvement of CLEC16A in endosomal trafficking and autolysosomal clearance, with accumulation of autophagosomes in Purkinje neurons of adult Clec16a knockout mice (Hain et al 2021;Redmann et al 2016). In addition, defective retromer-dependent trafficking results in accumulated autolysosomes (Seaman 2021).…”

Section: Clec16a Depletion In Zebrafish Results In Accumulated Autoly...mentioning

confidence: 99%

“…Clec16a knockout (KO) mice present with severe neurodegeneration, loss of cerebellar Purkinje cells associated with accumulated autophagosomes and activation of autophagy marker LC3 (Redmann et al 2016). Moreover, the impaired secretory capacity of Clec16a deficient neuronal cells induces ER stress in a conditional KO Clec16a mouse model (Hain et al 2021). The physiological ER stress response is essential during normal brain development by acting as a protective and intrinsic regulator of protein synthesis and metabolic homeostasis.…”

Section: Introductionmentioning

confidence: 99%

CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment

et al. 2022

View full text Add to dashboard Cite

CLEC16A is a membrane-associated C-type lectin protein that functions as a E3-ubiquitin ligase. CLEC16A regulates autophagy and mitophagy, and reportedly localizes to late endosomes. GWAS studies have associated CLEC16A SNPs to various auto-immune and neurological disorders, including multiple sclerosis and Parkinson disease. Studies in mouse models imply a role for CLEC16A in neurodegeneration. We identified bi-allelic CLEC16A truncating variants in siblings from unrelated families presenting with a severe neurodevelopmental disorder including microcephaly, brain atrophy, corpus callosum dysgenesis, and growth retardation. To understand the function of CLEC16A in neurodevelopment we used in vitro models and zebrafish embryos. We observed CLEC16A localization to early endosomes in HEK293T cells. Mass spectrometry of human CLEC16A showed interaction with endosomal retromer complex subunits and the endosomal ubiquitin ligase TRIM27. Expression of the human variant leading to C-terminal truncated CLEC16A, abolishes both its endosomal localization and interaction with TRIM27, suggesting a loss-of-function effect. CLEC16A knockdown increased TRIM27 adhesion to early endosomes and abnormal accumulation of endosomal F-actin, a sign of disrupted vesicle sorting. Mutagenesis of clec16a by CRISPR–Cas9 in zebrafish embryos resulted in accumulated acidic/phagolysosome compartments, in neurons and microglia, and dysregulated mitophagy. The autophagocytic phenotype was rescued by wild-type human CLEC16A but not the C-terminal truncated CLEC16A. Our results demonstrate that CLEC16A closely interacts with retromer components and regulates endosomal fate by fine-tuning levels of TRIM27 and polymerized F-actin on the endosome surface. Dysregulation of CLEC16A-mediated endosomal sorting is associated with neurodegeneration, but it also causes accumulation of autophagosomes and unhealthy mitochondria during brain development.

show abstract

“…These results suggest that activation of ISGs is a shared feature of neuronal injuries and that ISG15 may be a suitable biomarker for detecting neuronal injuries in the central nervous system (CNS) [196]. Consistent with these findings, upregulation of ISG15 was observed in neuronal tissues and has been linked to degeneration of sensory neurons in Clec16a knockout mice [197]. Together, these results suggest that elevated ISG15 is associated with neurodegeneration.…”

Section: Isg15 In Neurodegenerative Disordersmentioning

confidence: 63%

ISG15 and ISGylation in Human Diseases

Mirzalieva

Juncker

Schwartzenburg

et al. 2022

Cells

View full text Add to dashboard Cite

Type I Interferons (IFNs) induce the expression of >500 genes, which are collectively called ISGs (IFN-stimulated genes). One of the earliest ISGs induced by IFNs is ISG15 (Interferon-Stimulated Gene 15). Free ISG15 protein synthesized from the ISG15 gene is post‑translationally conjugated to cellular proteins and is also secreted by cells into the extracellular milieu. ISG15 comprises two ubiquitin-like domains (UBL1 and UBL2), each of which bears a striking similarity to ubiquitin, accounting for its earlier name ubiquitin cross-reactive protein (UCRP). Like ubiquitin, ISG15 harbors a characteristic β‑grasp fold in both UBL domains. UBL2 domain has a conserved C‑terminal Gly-Gly motif through which cellular proteins are appended via an enzymatic cascade similar to ubiquitylation called ISGylation. ISG15 protein is minimally expressed under physiological conditions. However, its IFN‑dependent expression is aberrantly elevated or compromised in various human diseases, including multiple types of cancer, neurodegenerative disorders (Ataxia Telangiectasia and Amyotrophic Lateral Sclerosis), inflammatory diseases (Mendelian Susceptibility to Mycobacterial Disease (MSMD), bacteriopathy and viropathy), and in the lumbar spinal cords of veterans exposed to Traumatic Brain Injury (TBI). ISG15 and ISGylation have both inhibitory and/or stimulatory roles in the etiology and pathogenesis of human diseases. Thus, ISG15 is considered a “double-edged sword” for human diseases in which its expression is elevated. Because of the roles of ISG15 and ISGylation in cancer cell proliferation, migration, and metastasis, conferring anti-cancer drug sensitivity to tumor cells, and its elevated expression in cancer, neurodegenerative disorders, and veterans exposed to TBI, both ISG15 and ISGylation are now considered diagnostic/prognostic biomarkers and therapeutic targets for these ailments. In the current review, we shall cover the exciting journey of ISG15, spanning three decades from the bench to the bedside.

show abstract

Inducible knockout of Clec16a in mice results in sensory neurodegeneration

Cited by 7 publications

References 70 publications

CLEC16A—An Emerging Master Regulator of Autoimmunity and Neurodegeneration

CLEC16A—An Emerging Master Regulator of Autoimmunity and Neurodegeneration

CLEC16A interacts with retromer and TRIM27, and its loss impairs endosomal trafficking and neurodevelopment

ISG15 and ISGylation in Human Diseases

Contact Info

Product

Resources

About