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

Research output: Contribution to journalResearch articleContributedpeer-review


  • Andrea Delle Vedove - , University of Cologne (Author)
  • Janani Natarajan - , Chair of Cellular Biochemistry (Author)
  • Ginevra Zanni - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Matthias Eckenweiler - , University of Freiburg (Author)
  • Anixa Muiños-Bühl - , University of Cologne (Author)
  • Markus Storbeck - , University of Cologne (Author)
  • Jordina Guillén Boixet - , Chair of Cellular Biochemistry (Author)
  • Sabina Barresi - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Simone Pizzi - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Irmgard Hölker - , University of Cologne (Author)
  • Friederike Körber - , Uniklinik Köln (Author)
  • Titus M. Franzmann - , Chair of Cellular Biochemistry (Author)
  • Enrico S. Bertini - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Janbernd Kirschner - , University of Freiburg (Author)
  • Simon Alberti - , Chair of Cellular Biochemistry (Author)
  • Marco Tartaglia - , IRCCS Ospedale pediatrico Bambino Gesù - Roma (Author)
  • Brunhilde Wirth - , University of Cologne (Author)


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.


Original languageEnglish
Article number526
JournalCellular and Molecular Life Sciences
Issue number10
Publication statusPublished - Oct 2022

External IDs

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


Research priority areas of TU Dresden

DFG Classification of Subject Areas according to Review Boards


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

Library keywords