FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy.

Abstract

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by motor neuron degeneration and associated with aggregation of nuclear RNA-binding proteins (RBPs), including FUS. How FUS aggregation and neurodegeneration are prevented in healthy motor neurons remain critically unanswered questions. Here, we use a combination of ALS patient autopsy tissue and induced pluripotent stem cell-derived neurons to study the effects of FUS mutations on RBP homeostasis. We show that FUS' tendency to aggregate is normally buffered by interacting RBPs, but this buffering is lost when FUS mislocalizes to the cytoplasm due to ALS mutations. The presence of aggregation-prone FUS in the cytoplasm causes imbalances in RBP homeostasis that exacerbate neurodegeneration. However, enhancing autophagy using small molecules reduces cytoplasmic FUS, restores RBP homeostasis and rescues motor function in vivo. We conclude that disruption of RBP homeostasis plays a critical role in FUS-ALS and can be treated by stimulating autophagy.

• Authors: Lara Marrone, Hannes C A Drexler, Jie Wang, Priyanka Tripathi, Tania Distler, Patrick Heisterkamp, Eric Nathaniel Anderson, Sukhleen Kour, Anastasia Moraiti, Shovamayee Maharana, Rajat Bhatnagar, T Grant Belgard, Vadreenath Tripathy, Norman Kalmbach, Zohreh Hosseinzadeh, Valeria Crippa, Masin Abo-Rady, Florian Wegner, Angelo Poletti, Dirk Troost, Eleonora Aronica, Volker Busskamp, Joachim Weis, Udai Bhan Pandey, Anthony A Hyman, Simon Alberti, Anand Goswami, Jared Sterneckert
• Journal: Acta neuropathologica (Acta Neuropathol) Vol. 138 Issue 1 Pg. 67-84 (07 2019) ISSN: 1432-0533 [Electronic] Germany
• PMID: 30937520 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• FUS protein, human
• RNA-Binding Protein FUS

Topics

• Amyotrophic Lateral Sclerosis (pathology)
• Autophagy (physiology)
• Cytoplasm (metabolism)
• Humans
• Inclusion Bodies (pathology)
• Induced Pluripotent Stem Cells (pathology)
• Motor Neurons (pathology)
• Mutation (genetics)
• RNA-Binding Protein FUS (metabolism)