Loss of PML nuclear bodies in familial amyotrophic lateral sclerosis-frontotemporal dementia

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Francesco Antoniani - , University of Modena and Reggio Emilia (Autor:in)
  • Marco Cimino - , University of Modena and Reggio Emilia (Autor:in)
  • Laura Mediani - , University of Modena and Reggio Emilia (Autor:in)
  • Jonathan Vinet - , University of Modena and Reggio Emilia (Autor:in)
  • Enza M. Verde - , University of Modena and Reggio Emilia (Autor:in)
  • Valentina Secco - , University of Modena and Reggio Emilia (Autor:in)
  • Alfred Yamoah - , RWTH Aachen University (Autor:in)
  • Priyanka Tripathi - , RWTH Aachen University (Autor:in)
  • Eleonora Aronica - , University of Amsterdam (Autor:in)
  • Maria E. Cicardi - , Thomas Jefferson University (Autor:in)
  • Davide Trotti - , Thomas Jefferson University (Autor:in)
  • Jared Sterneckert - , Professur für iPS Zellen und neurodegenerative Erkrankungen, Center for Regenerative Therapies Dresden (CRTD), Universitätsklinikum Carl Gustav Carus Dresden (Autor:in)
  • Anand Goswami - , RWTH Aachen University, Columbia University (Autor:in)
  • Serena Carra - , University of Modena and Reggio Emilia, Medizinische Fakultät Carl Gustav Carus Dresden (Autor:in)

Abstract

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share genetic causes and pathogenic mechanisms. The critical genetic players of ALS and FTD are the TARDBP, FUS and C9orf72 genes, whose protein products, TDP-43, FUS and the C9orf72-dipeptide repeat proteins, accumulate in form of cytoplasmic inclusions. The majority of the studies focus on the understanding of how cells control TDP-43 and FUS aggregation in the cytoplasm, overlooking how dysfunctions occurring at the nuclear level may influence the maintenance of protein solubility outside of the nucleus. However, protein quality control (PQC) systems that maintain protein homeostasis comprise a cytoplasmic and a nuclear arm that are interconnected and share key players. It is thus conceivable that impairment of the nuclear arm of the PQC may have a negative impact on the cytoplasmic arm of the PQC, contributing to the formation of the cytoplasmic pathological inclusions. Here we focused on two stress-inducible condensates that act as transient deposition sites for misfolding-prone proteins: Promyelocytic leukemia protein (PML) nuclear bodies (PML-NBs) and cytoplasmic stress granules (SGs). Upon stress, PML-NBs compartmentalize misfolded proteins, including defective ribosomal products (DRiPs), and recruit chaperones and proteasomes to promote their nuclear clearance. SGs transiently sequester aggregation-prone RNA-binding proteins linked to ALS-FTD and mRNAs to attenuate their translation. We report that PML assembly is impaired in the human brain and spinal cord of familial C9orf72 and FUS ALS-FTD cases. We also show that defective PML-NB assembly impairs the compartmentalization of DRiPs in the nucleus, leading to their accumulation inside cytoplasmic SGs, negatively influencing SG dynamics. Although it is currently unclear what causes the decrease of PML-NBs in ALS-FTD, our data highlight the existence of a cross-talk between the cytoplasmic and nuclear PQC systems, whose alteration can contribute to SG accumulation and cytoplasmic protein aggregation in ALS-FTD.

Details

OriginalspracheEnglisch
Aufsatznummer248
FachzeitschriftCell death discovery
Jahrgang9
Ausgabenummer1
PublikationsstatusVeröffentlicht - 15 Juli 2023
Peer-Review-StatusJa

Externe IDs

WOS 001031353700003
ORCID /0000-0002-7688-3124/work/142660132

Schlagworte

Ziele für nachhaltige Entwicklung

Schlagwörter

  • Motor-neuron disease, Hexanucleotide repeat, Misfolded proteins, Lobar degeneration, Phase-transition, Stress granules, Heat-shock, Als, Rna, Mechanisms