Evidence for the Deregulation of Protein Turnover Pathways in Atm-Deficient Mouse Cerebellum: An Organotypic Study

Kim, Catherine D.; Reed, Ryan E; Juncker, Meredith; Fang, Zhide; Desai, Shyamal D.

doi:10.1093/jnen/nlx038

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…Empirical evidence from our lab has revealed that ISGylation predominantly antagonizes the canonical ubiquitin pathway in cancer (10) and ataxia telangiectasia (A-T) (11), a rare neurodegenerative disease. Since polyubiquitylation of cellular proteins is a prerequisite for protein turnover via the 26S proteasome, and ubiquitin-mediated protein turnover is crucial in maintaining cellular homeostasis, ISG15 proteinopathy (ISG15-mediated defective protein turnover) is proposed to be an underlying cause of malignancy (10,12) and A-T neurodegeneration (11,13) in human and mouse experimental disease models.…”

Section: Introductionmentioning

confidence: 99%

Increased ISGylation in Cases of TBI-Exposed ALS Veterans

Schwartzenburg

Juncker

Reed

et al. 2018

Journal of Neuropathology &Amp; Experimental Neurology

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Veterans who have served in the military are at a nearly 60% greater risk of being diagnosed with amyotrophic lateral sclerosis (ALS). Literature reports suggest that a history of traumatic brain injury (TBI) may be a risk factor for ALS in veterans. However, no diagnostic biomarkers are available for identifying ALS risk/development in TBI-exposed veterans. Here, using a Wes assay, we show that ISGylation, a conjugated form of interferon-stimulated gene 15 protein, is significantly elevated in the lumbar spinal cords (SC-Ls) of TBI-ALS compared with ALS veterans without a previous history of TBI (nonTBI-ALS). Although not as striking as in TBI-ALS veterans, ISGylation is also increased in nonTBI-ALS compared with normal veterans. Notably, no changes in ISGylation were seen in occipital lobe samples obtained from the same patients, suggesting that elevated ISGylation is distinct to ALS disease-specific SC-Ls. Moreover, we detected increased ISGylation in cerebral spinal fluid samples of TBI-ALS veterans. Other results using cultured lymphocyte cell lines show a similar trend of increased ISGylation in ALS patients from the general population. Together, these data suggest that ISGylation could serve as a diagnostic biomarker for TBI-ALS veterans, nonTBI-ALS veterans, and nonveterans affected by ALS.

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Section: Introductionmentioning

confidence: 99%

Increased ISGylation in Cases of TBI-Exposed ALS Veterans

Schwartzenburg

Juncker

Reed

et al. 2018

Journal of Neuropathology &Amp; Experimental Neurology

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“…ISG15, a ubiquitin-like modifier that inhibits polyubiquitination and is involved in a post-translational modification process called ISGylation, has a role in autophagy by conjugating with other proteins to control clearance of protein aggregates 14 . Activation of ISIG15 occurs after cell stress 15 , when neuronal damage is present [16][17][18] , and is hypothesized to be a potential cause of defective mitophagy in neurodegenerative diseases 19 . ISG15 and ISGylation are implicated in the control of mitochondrial OXPHOS and recycling in bone marrow-derived macrophages 20 .…”

mentioning

confidence: 99%

Inducible knockout of Clec16a in mice results in sensory neurodegeneration

Hain

Pandey

Bakay

et al. 2021

Sci Rep

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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, Clec16aΔUBC 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.

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“…ISG15 is elevated in human A-T cells and mice. 26,122 Similarly, interferon signaling is also elevated in mutant SOD1 mice, 93,123 and specifically upregulated in their Figure 1. A proposed model for defective mitophagy in neurodegenerative diseases.…”

Section: Isg15 a Potential Modulator Of Mitophagy In Neurodegeneratimentioning

confidence: 93%

Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases

Desai

Juncker

Kim

2018

Exp Biol Med (Maywood)

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Mitophagy is a cellular process by which dysfunctional mitochondria are degraded via autophagy. Increasing empirical evidence proposes that this mitochondrial quality-control mechanism is defective in neurons of patients with various neurodegenerative diseases such as Ataxia Telangiectasia, Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Accumulation of defective mitochondria and the production of reactive oxygen species due to defective mitophagy have been identified as causes underlying neurodegenerative disease pathogenesis. However, the reason mitophagy is defective in most neurodegenerative diseases is unclear. Like mitophagy, defects in the ubiquitin/26S proteasome pathway have been linked to neurodegeneration, resulting in the characteristic protein aggregates often seen in neurons of affected patients. Although initiation of mitophagy requires a functional ubiquitin pathway, whether defects in the ubiquitin pathway are causally responsible for defective mitophagy is not known. In this mini-review, we introduce mitophagy and ubiquitin pathways and provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway. We will then briefly review empirical evidence supporting mitophagy defects in neurodegenerative diseases. The review will conclude with a discussion of the constitutively elevated expression of ubiquitin-like protein Interferon-Stimulated Gene 15 (ISG15), an antagonist of the ubiquitin pathway, as a potential cause of defective mitophagy in neurodegenerative diseases. Impact statement Neurodegenerative diseases place an enormous burden on patients and caregivers globally. Over six million people in the United States alone suffer from neurodegenerative diseases, all of which are chronic, incurable, and with causes unknown. Identifying a common molecular mechanism underpinning neurodegenerative disease pathology is urgently needed to aid in the design of effective therapies to ease suffering, reduce economic cost, and improve the quality of life for these patients. Although the development of neurodegeneration may vary between neurodegenerative diseases, they have common cellular hallmarks, including defects in the ubiquitin-proteasome system and mitophagy. In this review, we will provide a summary of our current understanding of the regulation of mitophagy by the ubiquitin pathway and discuss the potential of targeting mitophagy and ubiquitin pathways for the treatment of neurodegeneration.

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Evidence for the Deregulation of Protein Turnover Pathways in Atm-Deficient Mouse Cerebellum: An Organotypic Study

Cited by 8 publications

References 32 publications

Increased ISGylation in Cases of TBI-Exposed ALS Veterans

Increased ISGylation in Cases of TBI-Exposed ALS Veterans

Inducible knockout of Clec16a in mice results in sensory neurodegeneration

Regulation of mitophagy by the ubiquitin pathway in neurodegenerative diseases

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