Delle Vedove, Andrea, Natarajan, Janani, Zanni, Ginevra, Eckenweiler, Matthias, Muinos-Buehl, Anixa, Storbeck, Markus, Boixet, Jordina Guillen, Barresi, Sabina, Pizzi, Simone, Hoelker, Irmgard, Koerber, Friederike, Franzmann, Titus M., Bertini, Enrico S., Kirschner, Janbernd ORCID: 0000-0003-1618-7386, Alberti, Simon, Tartaglia, Marco and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2022). CAPRIN1(P512L) causes aberrant protein aggregation and associates with early-onset ataxia. Cell. Mol. Life Sci., 79 (10). BASEL: SPRINGER BASEL AG. ISSN 1420-9071

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Abstract

CAPRIN1 is a ubiquitously expressed protein, abundant in the brain, where it regulates the transport and translation of mRNAs of genes involved in synaptic plasticity. Here we describe two unrelated children, who developed early-onset ataxia, dysarthria, cognitive decline and muscle weakness. Trio exome sequencing unraveled the identical de novo c.1535C > T (p.Pro512Leu) missense variant in CAPRIN1, affecting a highly conserved residue. In silico analyses predict an increased aggregation propensity of the mutated protein. Indeed, overexpressed CAPRIN1(P512L) forms insoluble ubiquitinated aggregates, sequestrating proteins associated with neurodegenerative disorders (ATXN2, GEMIN5, SNRNP200 and SNCA). Moreover, the CAPRIN1(P512L) mutation in isogenic iPSC-derived cortical neurons causes reduced neuronal activity and altered stress granule dynamics. Furthermore, nano-differential scanning fluorimetry reveals that CAPRIN1(P512L) aggregation is strongly enhanced by RNA in vitro. These findings associate the gain-of-function Pro512Leu mutation to early-onset ataxia and neurodegeneration, unveiling a critical residue of CAPRIN1 and a key role of RNA-protein interactions.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Delle Vedove, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Natarajan, JananiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zanni, GinevraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eckenweiler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muinos-Buehl, AnixaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Storbeck, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boixet, Jordina GuillenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barresi, SabinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pizzi, SimoneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelker, IrmgardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koerber, FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franzmann, Titus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertini, Enrico S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirschner, JanberndUNSPECIFIEDorcid.org/0000-0003-1618-7386UNSPECIFIED
Alberti, SimonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tartaglia, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
URN: urn:nbn:de:hbz:38-683110
DOI: 10.1007/s00018-022-04544-3
Journal or Publication Title: Cell. Mol. Life Sci.
Volume: 79
Number: 10
Date: 2022
Publisher: SPRINGER BASEL AG
Place of Publication: BASEL
ISSN: 1420-9071
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PRION-LIKE DOMAINS; RNA-BINDING PROTEINS; FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; STRESS GRANULE; SUBCELLULAR ORGANIZATION; TREMOR/ATAXIA SYNDROME; PHASE-TRANSITION; DISEASE; MUTATIONSMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68311

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