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.
Highlights
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease [28]
When we immunostained human spinal cord tissue from ALS patients carrying the Fused in sarcoma (FUS)-nuclear localization signal (NLS) mutation R521C, we found that the lumbar spinal cord of FUSALS cases showed severe loss of α-MNs [suppl
When we focused on ALS-associated proteins, we found that a number of FUS interaction partners encompassed RNA-binding proteins (RBPs) previously described to cause familial forms of ALS, including heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), hnRNPA2B1, Ewing sarcoma breakpoint region 1 (EWSR1) and TATA-Box Binding Protein Associated Factor 15 (TAF15), were reduced in pulldown samples with P525L FUS compared to WT
Summary
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease [28]. 10% of all ALS cases are familial, many of which have been linked to genetic mutations in RNA-binding proteins (RBPs), including Fused in sarcoma (FUS), TAR DNA-binding protein 43 (TDP43), Matrin, Ewing sarcoma breakpoint region 1 (EWSR1), TATA-Box Binding Protein Associated Factor 15 (TAF15), heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), hnRNPA2B1, and TIA1 [15] These RBPs are structurally related, containing at least one RNA-recognition motif (RRM), a nuclear localization signal (NLS), and a low complexity domain, which is required for phase separation. Answering these questions should contribute to the development of effective therapeutics for ALS patients In this manuscript, we use a combination of neuropathology and induced pluripotent stem cell (iPSC)-derived neurons to study the effects of FUS mutations on protein homeostasis. Since impaired homeostasis is a hallmark of multiple ALS subtypes, drugs inducing autophagy could be effective therapeutics for many ALS patients
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