FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:138 |
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| Enthalten in: |
Acta neuropathologica - 138(2019), 1 vom: 01. Juli, Seite 67-84 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marrone, Lara [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.07.2020 Date Revised 21.07.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00401-019-01998-x |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM295594926 |
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| 245 | 1 | 0 | |a FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy |
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| 500 | |a Date Revised 21.07.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Amyotrophic lateral sclerosis | |
| 650 | 4 | |a FUS | |
| 650 | 4 | |a Induced pluripotent stem cells | |
| 650 | 4 | |a Phase transition | |
| 650 | 4 | |a Protein homeostasis | |
| 650 | 4 | |a RNA-binding proteins | |
| 650 | 7 | |a FUS protein, human |2 NLM | |
| 650 | 7 | |a RNA-Binding Protein FUS |2 NLM | |
| 700 | 1 | |a Drexler, Hannes C A |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Tripathi, Priyanka |e verfasserin |4 aut | |
| 700 | 1 | |a Distler, Tania |e verfasserin |4 aut | |
| 700 | 1 | |a Heisterkamp, Patrick |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, Eric Nathaniel |e verfasserin |4 aut | |
| 700 | 1 | |a Kour, Sukhleen |e verfasserin |4 aut | |
| 700 | 1 | |a Moraiti, Anastasia |e verfasserin |4 aut | |
| 700 | 1 | |a Maharana, Shovamayee |e verfasserin |4 aut | |
| 700 | 1 | |a Bhatnagar, Rajat |e verfasserin |4 aut | |
| 700 | 1 | |a Belgard, T Grant |e verfasserin |4 aut | |
| 700 | 1 | |a Tripathy, Vadreenath |e verfasserin |4 aut | |
| 700 | 1 | |a Kalmbach, Norman |e verfasserin |4 aut | |
| 700 | 1 | |a Hosseinzadeh, Zohreh |e verfasserin |4 aut | |
| 700 | 1 | |a Crippa, Valeria |e verfasserin |4 aut | |
| 700 | 1 | |a Abo-Rady, Masin |e verfasserin |4 aut | |
| 700 | 1 | |a Wegner, Florian |e verfasserin |4 aut | |
| 700 | 1 | |a Poletti, Angelo |e verfasserin |4 aut | |
| 700 | 1 | |a Troost, Dirk |e verfasserin |4 aut | |
| 700 | 1 | |a Aronica, Eleonora |e verfasserin |4 aut | |
| 700 | 1 | |a Busskamp, Volker |e verfasserin |4 aut | |
| 700 | 1 | |a Weis, Joachim |e verfasserin |4 aut | |
| 700 | 1 | |a Pandey, Udai Bhan |e verfasserin |4 aut | |
| 700 | 1 | |a Hyman, Anthony A |e verfasserin |4 aut | |
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| 700 | 1 | |a Goswami, Anand |e verfasserin |4 aut | |
| 700 | 1 | |a Sterneckert, Jared |e verfasserin |4 aut | |
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