Maintenance of mRNA and protein localization in motor neurons is a potential therapeutic avenue for Amyotrophic lateral sclerosis (ALS), report researchers from The Francis Crick Institute and the University College London (UCL). A new study shows how the extensive changes in mRNA and protein in ALS motor neurons are linked to mutations in an ATPase called VCP. These mutations may contribute to the mislocalization of RNA binding proteins (RBPs) that tend to clump together and the redistribution of the mRNAs they are bound to. Inhibition of VCP partly restored mRNA and protein localization and other ALS phenotypes. These results show how RBP mislocalization and mRNA redistribution in motor neurons are linked to ALS and how VCP inhibition could be used as a treatment.

The study “Nucleocytoplasmic mRNA redistribution accompanies RNA binding protein mislocalization in ALS motor neurons and is restored by VCP ATPase inhibition” was published today in Neuron.

“For the patients I see, it’s devastating that there aren’t yet impactful treatments available for ALS,” said Rickie Patani, PhD, senior group leader of the Human Stem Cells and Neurodegeneration Laboratory at the Crick, professor at UCL, and consultant neurologist at the National Hospital for Neurology. “This research represents a shift in our thinking about what causes ALS—it doesn’t involve abnormal movement of just a few proteins, but the abnormal localization of hundreds of proteins and mRNAs. This opens new avenues for research and potential therapies.

RBP mislocalization and mRNA redistribution in ALS motor neurons 

ALS is characterized by nucleocytoplasmic mislocalization of the RBP TDP-43. Recent discoveries, however, point to a much wider problem of mRNA and protein mislocalization. In addition, whether or not RBP mislocalization leads to mRNA redistribution in ALS has been largely overlooked. Recent research has found that mutations in mRNA export factors could be a cause of ALS, adding to the growing body of evidence that links ALS to problems with nucleocytoplasmic transport. 

Lead author Oliver J. Ziff and his colleagues used induced motor neurons from healthy people and ALS patients with TARDBP and VCP mutations to study how the transcriptome and proteome are distributed inside cells. The induced motor neurons from ALS patients caused significant changes to the mRNA, RBP, and splicing in the motor neurons’ nuclei and cytoplasm. The results also support the idea that RNA processing and interactions with RBPs are essential for mRNA redistribution because they found that redistributed transcripts were more likely to have longer 3′ UTRs, RBP interactions, and splicing flaws.

Ziff, Clinician Scientist at the Crick and UCLH, said: “We were surprised to see the extent of the mislocalization, particularly for mRNAs, as this hasn’t been reported before. The goal now is to find where this problem starts, and there are many intriguing possibilities—one being a breakdown in the transport between the nucleus and cytoplasm. This study was an exceptional team effort, and I’m immensely grateful to my colleagues, particularly co-first authors Jasmine Harley, Yiran Wang, and Jacob Neeves.”

Therapeutic potential of VCP inhibition

The research team went a step further and found that treatment with ML240, a VCP ATPase inhibitor, partially restored mRNA and protein localization in ALS mutant iPSMNs. ML240 induced changes in the VCP interactome and lysosomal localization and reduced oxidative stress and DNA damage. These findings highlight the therapeutic potential of VCP inhibition.

“As ML240 improved the mislocalization and other disease features in ALS, we now need to understand if this can be a tractable therapy for ALS more widely,” said Patani. “This is just the beginning, and there is lots more to do, but our work provides some hope for effective therapies.”

Although iPSMNs provide a disease-relevant cell type, there are inherent differences between in vitro cultures and in vivo tissues. While Ziff and colleagues attempted to compare redistributed transcripts in iPSMNs with differentially expressed transcripts in postmortem tissue, this comparison was limited because bulk RNA sequencing of spinal cord tissue comprises a mixture of various cell types and is not motor neuron-specific. Additionally, the postmortem samples were not subjected to fractionation, which limited their ability to determine the nucleocytoplasmic transcript distributions.

The researchers suggest that future research should aim to validate these findings across different ALS genetic backgrounds and models. Despite these limitations, this study provides valuable mechanistic insights into the pathogenesis of ALS and highlights a potential therapeutic avenue.

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