<i>TRIM25</i> mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early‐onset autosomal dominant dementia with amyloid load and parkinsonism

Gómez‐Tortosa, Estrella; Baradaran‐Heravi, Yalda; Dillen, Lubina; Choudhury, Nila Roy; Agüero Rabes, Pablo; Pérez‐Pérez, Julián; Kocoglu, Cemile; Sainz, M. José; Ruiz González, Alicia; Téllez, Raquel; Cremades‐Jimeno, Lucía; Cárdaba, Blanca; ,; Van Broeckhoven, Christine; Michlewski, Gracjan; van der Zee, Julie

doi:10.1002/alz.12913

Cited by 5 publications

(2 citation statements)

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“…CpG methylation on HERC5 gene, suggesting its downregulation is seen in late-onset AD cases, when compared with the normal controls [73]. A mutation in TRIM25 is associated with early-onset autosomal dominant dementia and amyloidogenesis [74]. Further, RNA-seq data suggests low abundance of HERC5 and TRIM25 in brain samples analysed from individuals with aging, dementia or with traumatic brain injury, when compared with healthy subjects [75].…”

Section: Discussionmentioning

confidence: 99%

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

Das,

Chakrabarti

2024

Cell Death Dis

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Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer’s disease pathophysiology.

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Section: Discussionmentioning

confidence: 99%

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

Das,

Chakrabarti

2024

Cell Death Dis

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“… 20 Previous study has shown that Trim25 , coding for an E3 ubiquitin ligase, is associated with AD and PD through a loss-of-function mechanism, suggesting its potential as a biomarker. 55 …”

Section: Discussionmentioning

confidence: 99%

Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2

Paul,

Dansithong,

Gandelman

et al. 2024

Neurol Genet

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Background and Objectives Micro-RNAs (miRNAs) are critical for regulating the expression of genes in multiple neurodegenerative diseases, but miRNAs have not been investigated in spinocerebellar ataxia type 2 (SCA2). SCA2, a dominantly inherited progressive neurodegenerative polyglutamine (polyQ) disease, is caused by a CAG repeat expansion in the ataxin-2 ( ATXN2 ) gene. In this study, we determined miRNA transcriptomes in SCA2-BAC- ATXN2[Q72] transgenic mice. Methods We assessed the expression of miRNAs in SCA2 transgenic mouse cerebella using the HiSeq Illumina sequencer. We used the miRNA target filter tool in Qiagen Ingenuity Pathway Analysis (IPA) to identify target genes of differentially expressed miRNAs (DEmiRs) within in the SCA2 mouse transcriptomes and then performed pathway analyses. Results Our analysis revealed significant changes in the expression levels of multiple miRNAs in mice with SCA2. We identified 81 DEmiRs in mice with SCA2, with 52 miRNAs upregulated and 29 miRNAs downregulated after onset of rotarod deficit. Subsequent IPA processing enabled us to establish connections between these DEmiRs and specific biological regulatory functions. Furthermore, by using the IPA miRNA target filter, we identified target genes of DEmiRs in the SCA2-BAC- ATXN2[Q72] transcriptome data set and demonstrated their significant impact on several biological functional and disease pathways. Discussion Our study establishes the role of both DEmiRs and their targets in SCA2 pathogenesis. By expressing mutant ATXN2 under the control of its endogenous regulatory elements in the SCA2-BAC- ATXN2[Q72] mouse model , we identified a set of DEmiRs that are shared across multiple neurodegenerative diseases including other SCAs, Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). There was a significant overlap of both DEmiRs and their targets of BAC- ATXN2[Q72] transcriptomes in dysregulated pathways that characterize SCA2. This observation also extended to dysregulated pathways in ALS, AD, and PD. DEmiRs identified in this study may represent therapeutic targets for neurodegeneration or lead to biomarkers for characterizing various neurodegenerative diseases.

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Risperidone

2023

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TRIM25 mutation (p.C168*), coding for an E3 ubiquitin ligase, is a cause of early‐onset autosomal dominant dementia with amyloid load and parkinsonism

Cited by 5 publications

References 50 publications

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

Cerebellar Micro-RNA Profile in a Mouse Model of Spinocerebellar Ataxia Type 2

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