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

Cell Death Discov. 2023 Jul 15;9(1):248. doi: 10.1038/s41420-023-01547-2.

Francesco Antoniani ^# ¹, Marco Cimino ^# ¹, Laura Mediani ¹, Jonathan Vinet ², Enza M Verde ¹, Valentina Secco ¹, Alfred Yamoah ³, Priyanka Tripathi ³, Eleonora Aronica ⁴, Maria E Cicardi ⁵, Davide Trotti ⁵, Jared Sterneckert ⁶ ⁷, Anand Goswami ⁸ ⁹ ¹⁰, Serena Carra ¹¹ ¹²

Affiliations

1 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
2 Centro Interdipartimentale Grandi Strumenti (CIGS), University of Modena and Reggio Emilia, Modena, Italy.
3 Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
4 Amsterdam UMC location University of Amsterdam, Department of (Neuro)Pathology, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, the Netherlands.
5 Weinberg ALS Center, Vickie and Jack Farber Institute for Neuroscience, Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
6 Center for Regenerative Therapies TU Dresden, Technische Universität Dresden, Dresden, Germany.
7 Medical Faculty Carl Gustav Carus of TU Dresden, Dresden, Germany.
8 Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany. ag4755@cumc.columbia.edu.
9 Department of Neurology, Center for Motor Neuron Biology and Disease, Columbia University, 10032, New York, NY, USA. ag4755@cumc.columbia.edu.
10 Department of Neurology, Eleanor and Lou Gehrig ALS Center, Columbia University, 10032, New York, NY, USA. ag4755@cumc.columbia.edu.
11 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy. serena.carra@unimore.it.
12 Medical Faculty Carl Gustav Carus of TU Dresden, Dresden, Germany. serena.carra@unimore.it.
# Contributed equally.

PMID: 37454169 DOI: 10.1038/s41420-023-01547-2

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.

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