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Research Articles, Neurobiology of Disease

Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy

Julia E. Gerson, Stephanie Sandoval-Pistorius, Jacqueline P. Welday, Aleija Rodriguez, Jordan D. Gregory, Nyjerus Liggans, Kylie Schache, Xingli Li, Hanna Trzeciakiewicz, Sami Barmada, Lisa M. Sharkey and Henry L. Paulson
Journal of Neuroscience 2 March 2022, 42 (9) 1845-1863; DOI: https://doi.org/10.1523/JNEUROSCI.1116-21.2021
Julia E. Gerson
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Stephanie Sandoval-Pistorius
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
2Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan 48109-2215
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Jacqueline P. Welday
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Aleija Rodriguez
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Jordan D. Gregory
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Nyjerus Liggans
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Kylie Schache
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Xingli Li
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Hanna Trzeciakiewicz
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Sami Barmada
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Lisa M. Sharkey
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Henry L. Paulson
1Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109-5316
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Abstract

Tau protein accumulation drives toxicity in several neurodegenerative disorders. To better understand the pathways regulating tau homeostasis in disease, we investigated the role of ubiquilins (UBQLNs)—a class of proteins linked to ubiquitin-mediated protein quality control (PQC) and various neurodegenerative diseases—in regulating tau. Cell-based assays identified UBQLN2 as the primary brain-expressed UBQLN to regulate tau. UBQLN2 efficiently lowered wild-type tau levels regardless of aggregation, suggesting that UBQLN2 interacts with and regulates tau protein under normal conditions or early in disease. Moreover, UBQLN2 itself proved to be prone to accumulation as insoluble protein in male and female tau transgenic mice and the human tauopathy progressive supranuclear palsy. Genetic manipulation of UBQLN2 in a tauopathy mouse model demonstrated that a physiological UBQLN2 balance is required for tau homeostasis. UBQLN2 overexpression exacerbated phosphorylated tau pathology and toxicity in mice expressing P301S mutant tau, whereas P301S mice lacking UBQLN2 showed significantly reduced phosphorylated tau. Further studies support the view that an imbalance of UBQLN2 perturbs ubiquitin-dependent PQC and autophagy. We conclude that changes in UBQLN2 levels, whether because of pathogenic mutations or secondary to disease states, such as tauopathy, contribute to proteostatic imbalances that exacerbate neurodegeneration.

SIGNIFICANCE STATEMENT We defined a role for the protein quality control protein Ubiquilin-2 (UBQLN2), in age-related neurodegenerative tauopathies. This group of disorders is characterized by the accumulation of tau protein aggregates, which differ when UBQLN2 levels are altered. Given the lack of effective disease-modifying therapies for tauopathies and the function of UBQLN2 in handling various disease-linked proteins, we explored the role of UBQLN2 in regulating tau. We found that UBQLN2 reduced tau levels in cell models but behaved differently in mouse brain, where it accelerated mutant tau pathology and tau-mediated toxicity. A better understanding of the diverse functions of regulatory proteins like UBQLN2 can elucidate some of the causative factors in neurodegenerative disease and outline new routes to therapeutic intervention.

  • aggregation
  • autophagy
  • proteostasis
  • tau
  • ubiquitin proteasome system
  • UBQLN2

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The Journal of Neuroscience: 42 (9)
Journal of Neuroscience
Vol. 42, Issue 9
2 Mar 2022
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Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy
Julia E. Gerson, Stephanie Sandoval-Pistorius, Jacqueline P. Welday, Aleija Rodriguez, Jordan D. Gregory, Nyjerus Liggans, Kylie Schache, Xingli Li, Hanna Trzeciakiewicz, Sami Barmada, Lisa M. Sharkey, Henry L. Paulson
Journal of Neuroscience 2 March 2022, 42 (9) 1845-1863; DOI: 10.1523/JNEUROSCI.1116-21.2021

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Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy
Julia E. Gerson, Stephanie Sandoval-Pistorius, Jacqueline P. Welday, Aleija Rodriguez, Jordan D. Gregory, Nyjerus Liggans, Kylie Schache, Xingli Li, Hanna Trzeciakiewicz, Sami Barmada, Lisa M. Sharkey, Henry L. Paulson
Journal of Neuroscience 2 March 2022, 42 (9) 1845-1863; DOI: 10.1523/JNEUROSCI.1116-21.2021
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Keywords

  • aggregation
  • autophagy
  • proteostasis
  • tau
  • ubiquitin proteasome system
  • UBQLN2

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