TRIM11 Prevents and Reverses Protein Aggregation and Rescues a Mouse Model of Parkinson’s Disease

Zhu, Guixin; Harischandra, Dilshan S.; Ghaisas, Shivani; Zhang, Pengfei; Prall, Wil; Huang, Liangqian; Maghames, Chantal; Guo, Lili; Luna, Esteban; Mack, Korrie L.; Torrente, Mariana P.; Luk, Kelvin C.; Shorter, James; Yang, Xiaolu

doi:10.1016/j.celrep.2020.108418

Cited by 43 publications

(55 citation statements)

References 71 publications

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“…TRIMs are exclusively metazoan, with over 70 distinct variants in humans ( Zhang et al, 2020 ). Remarkably, TRIM11 abrogates the aggregation of diverse proteins and solubilizes preformed aggregates, including neurotoxic amyloids formed by α-synuclein and polyQ ( Zhu et al, 2020 ). These activities can be separated from TRIM11 SUMO-ligase activity, but, when combined, they can promote the degradation of misfolded proteins ( Zhu et al, 2020 ).…”

Section: Tripartite Motif Proteins (Trims)mentioning

confidence: 99%

“…Remarkably, TRIM11 abrogates the aggregation of diverse proteins and solubilizes preformed aggregates, including neurotoxic amyloids formed by α-synuclein and polyQ ( Zhu et al, 2020 ). These activities can be separated from TRIM11 SUMO-ligase activity, but, when combined, they can promote the degradation of misfolded proteins ( Zhu et al, 2020 ). Importantly, TRIM11 dissolves α-synuclein fibrils in vitro and suppresses α-synuclein toxicity in cell and mouse models of PD.…”

Section: Tripartite Motif Proteins (Trims)mentioning

confidence: 99%

“…Importantly, TRIM11 dissolves α-synuclein fibrils in vitro and suppresses α-synuclein toxicity in cell and mouse models of PD. Indeed, intracranial delivery of adeno-associated viruses expressing TRIM11 suppressed prion-like spread of α-synuclein pathology, neurodegeneration and motor impairments in a PD mouse model ( Zhu et al, 2020 ). The ability of TRIM11 to mitigate these phenotypes indicates that TRIM11 does not release toxic α-synuclein species, unlike some circumstances for the previously discussed Hsp110, Hsp70 and Hsp40 system ( Tittelmeier et al, 2020 ).…”

Section: Tripartite Motif Proteins (Trims)mentioning

confidence: 99%

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(Dis)Solving the problem of aberrant protein states

Fare

Shorter

2021

Disease Models &Amp; Mechanisms

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Neurodegenerative diseases and other protein-misfolding disorders represent a longstanding biomedical challenge, and effective therapies remain largely elusive. This failure is due, in part, to the recalcitrant and diverse nature of misfolded protein conformers. Recent work has uncovered that many aggregation-prone proteins can also undergo liquid–liquid phase separation, a process by which macromolecules self-associate to form dense condensates with liquid properties that are compositionally distinct from the bulk cellular milieu. Efforts to combat diseases caused by toxic protein states focus on exploiting or enhancing the proteostasis machinery to prevent and reverse pathological protein conformations. Here, we discuss recent advances in elucidating and engineering therapeutic agents to combat the diverse aberrant protein states that underlie protein-misfolding disorders.

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Section: Tripartite Motif Proteins (Trims)mentioning

confidence: 99%

Section: Tripartite Motif Proteins (Trims)mentioning

confidence: 99%

Section: Tripartite Motif Proteins (Trims)mentioning

confidence: 99%

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(Dis)Solving the problem of aberrant protein states

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Shorter

2021

Disease Models &Amp; Mechanisms

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“…As SUMO plays a major role in regulating protein aggregation, including aggregation of mHTT [60,84,86,[112][113][114][115], we also analyzed the aggregated and soluble forms of mHTT by immunohistochemistry (IHC) and western blotting. We used EM48 antibody, the most (which was not certified by peer review) is the author/funder.…”

Section: Sumo1 Deletion Enhances Em48+ Aggregates and Decreases Solubmentioning

confidence: 99%

“…As SUMO plays a major role in regulating protein aggregation, including aggregation of mHTT [60,84,86,[112][113][114][115], we also analyzed the aggregated and soluble forms of mHTT by immunohistochemistry (IHC) and western blotting. We used EM48 antibody, the most sensitive antibody for detecting mHTT inclusions [116,117], as well as MAB2166 (clone 1HU-4C8) [117,118] and polyQ (clone 3B5H10) [119,120] antibodies to detect FL-HTT.…”

Section: Sumo1 Deletion Enhances Em48+ Aggregates and Decreases Solubmentioning

confidence: 99%

Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

Ramírez-Jarquín

Sharma

Shahani

et al. 2021

Preprint

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Mutant HTT (mHTT) associated with Huntington disease (HD) affects the central nervous system by prominent atrophy in the striatum and promotes psychiatric, cognitive, and choreiform movements, although the exact mechanism remains obscure. Previous studies have shown that SUMO1 (Small Ubiquitin-like Modifier-1) modification of mHTT promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knock-in mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions, while increasing cytoplasmic inclusions in the striatum of HD mice. SUMO1 deletion also enhanced autophagic activity, characterized by augmented interactions between mHTT inclusions and a lysosomal marker (LAMP1), increased LC3B/LAMP1 interaction, and decreased sequestosome-1 (p62) and mHTT and diminished p62/LAMP1 interactions in DARPP-32 positive medium spiny neurons (MSNs) in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by improving autophagy activities.

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Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

Cupo,

Shorter

2024

Israel Journal of Chemistry

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Protein folding is important for all life. Indeed, protein misfolding can result in catastrophic protein aggregation and toxicity. The pathways involved in reversing protein aggregation within human mitochondria had long been unknown. We recently discovered that Skd3 (human CLPB) is a potent mitochondrial protein disaggregase, which is regulated by the rhomboid protease PARL, and maintains the solubility of many important mitochondrial proteins. Skd3 variants underlie several debilitating human diseases, including 3‐methylglutaconic aciduria, severe congenital neutropenia, and premature ovarian insufficiency. Here, we describe advances in understanding Skd3 function, mechanism, and structure and place these discoveries in the context of physiology and disease.

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TRIM11 Prevents and Reverses Protein Aggregation and Rescues a Mouse Model of Parkinson’s Disease

Cited by 43 publications

References 71 publications

(Dis)Solving the problem of aberrant protein states

(Dis)Solving the problem of aberrant protein states

Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

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