CAPRIN1P512L causes aberrant protein aggregation and associates with early-onset ataxia

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Andrea Delle Vedove - , Universität zu Köln (Autor:in)
  • Janani Natarajan - , Professur für Zelluläre Biochemie (Autor:in)
  • Ginevra Zanni - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Autor:in)
  • Matthias Eckenweiler - , Albert-Ludwigs-Universität Freiburg (Autor:in)
  • Anixa Muiños-Bühl - , Universität zu Köln (Autor:in)
  • Markus Storbeck - , Universität zu Köln (Autor:in)
  • Jordina Guillén Boixet - , Professur für Zelluläre Biochemie (Autor:in)
  • Sabina Barresi - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Autor:in)
  • Simone Pizzi - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Autor:in)
  • Irmgard Hölker - , Universität zu Köln (Autor:in)
  • Friederike Körber - , Universitätsklinikum Köln (Autor:in)
  • Titus M. Franzmann - , Professur für Zelluläre Biochemie (Autor:in)
  • Enrico S. Bertini - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Autor:in)
  • Janbernd Kirschner - , Albert-Ludwigs-Universität Freiburg (Autor:in)
  • Simon Alberti - , Professur für Zelluläre Biochemie (Autor:in)
  • Marco Tartaglia - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Autor:in)
  • Brunhilde Wirth - , Universität zu Köln (Autor:in)


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 CAPRIN1P512L forms insoluble ubiquitinated aggregates, sequestrating proteins associated with neurodegenerative disorders (ATXN2, GEMIN5, SNRNP200 and SNCA). Moreover, the CAPRIN1P512L mutation in isogenic iPSC-derived cortical neurons causes reduced neuronal activity and altered stress granule dynamics. Furthermore, nano-differential scanning fluorimetry reveals that CAPRIN1P512L 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.


FachzeitschriftCellular and Molecular Life Sciences
PublikationsstatusVeröffentlicht - Okt. 2022

Externe IDs

PubMed 36136249
ORCID /0000-0003-4017-6505/work/142253849


Forschungsprofillinien der TU Dresden

DFG-Fachsystematik nach Fachkollegium


  • CRISPR/Cas9, De novo variant, Neurodegeneration, Prion-like domain, Protein misfolding, Protein Aggregates, Humans, Cell Cycle Proteins/metabolism, Ataxia, Mutation, Child, RNA, Messenger/metabolism