Autism Candidate Gene RBM-26 Regulates MALSU-1 to Protect Mitochondria and Prevent Axon Degeneration During Neurodevelopment

Core Concepts

RBM-26, the C. elegans ortholog of the autism candidate gene RBM27, protects against axonal defects by negatively regulating the expression of the MALS-1 mitoribosomal assembly factor.

Abstract

The content investigates the role of the RBM-26 (RBM26/27) RNA-binding protein in protecting against mitochondrial dysfunction and axon degeneration during neurodevelopment. Key insights:

1. RBM-26 is the C. elegans ortholog of the RBM27 autism candidate gene, and its function in neurons was previously unknown.

2. RBM-26 protects against axonal defects, such as axon tiling and degeneration, by negatively regulating the expression of the MALS-1 mitoribosomal assembly factor.

3. Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression, leading to the observed axon degeneration defects during larval development.

4. A biochemical screen identified the mRNA for the MALS-1 mitoribosomal assembly factor as a binding partner for RBM-26.

5. Loss of RBM-26 function causes a dramatic overexpression of mals-1 mRNA and MALS-1 protein, and this overexpression of MALS-1 is responsible for the mitochondrial and axon degeneration defects in rbm-26 mutants.

6. The findings reveal a mechanism that regulates the expression of a mitoribosomal assembly factor to protect against axon degeneration during neurodevelopment, which has implications for understanding the molecular basis of neurodevelopmental disorders like autism.

Stats

Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression.
Loss of RBM-26 function causes a dramatic overexpression of mals-1 mRNA and MALS-1 protein.

Quotes

"RBM-26 (RBM26/27) protects against axonal defects by negatively regulating expression of the MALS-1 (MALSU1) mitoribosomal assembly factor."
"Autism-associated missense variants in RBM-26 cause a sharp decrease in RBM-26 protein expression along with defects in in axon tiling and axon degeneration that occurs during larval development."

Key Insights Distilled From

Autism candidate gene rbm-26(RBM26/27) regulates MALS-1 to protect against mitochondrial dysfunction and axon degeneration during neurodevelopment.

by Chowdhury,T.... at www.biorxiv.org 10-14-2023

https://www.biorxiv.org/content/10.1101/2023.10.12.562060v2

Deeper Inquiries

What other molecular pathways or factors might be involved in regulating mitochondrial function and axon development during neurodevelopment?

Mitochondrial function and axon development during neurodevelopment are complex processes that involve a network of molecular pathways and factors. One key pathway is the PINK1/Parkin pathway, which plays a crucial role in maintaining mitochondrial quality control through mitophagy. Disruption of this pathway can lead to mitochondrial dysfunction and subsequent axonal degeneration. Additionally, the mTOR pathway is involved in regulating mitochondrial biogenesis and function, impacting axon growth and maintenance. Neurotrophic factors such as BDNF and NGF also play a role in promoting mitochondrial health and axon development by supporting energy metabolism and providing trophic support to neurons. Furthermore, calcium signaling pathways, oxidative stress response pathways, and mitochondrial dynamics regulators like Drp1 and Opa1 are also implicated in maintaining mitochondrial function and axon integrity during neurodevelopment.

How do the autism-associated RBM-26 variants mechanistically lead to the observed decrease in protein expression?

Autism-associated RBM-26 variants can mechanistically lead to the observed decrease in protein expression through various mechanisms. One possible mechanism is that these variants may disrupt the RNA-binding ability of RBM-26, affecting its interaction with target mRNAs such as MALS-1. This disruption could lead to aberrant mRNA stability or translation, resulting in reduced RBM-26 protein levels. Additionally, these variants may impact the protein's stability or post-translational modifications, leading to accelerated degradation or impaired function. Furthermore, the variants could affect the splicing or processing of RBM-26 mRNA, resulting in the production of non-functional or unstable protein isoforms. Overall, these mechanisms collectively contribute to the decreased protein expression of RBM-26, ultimately impacting its regulatory role in protecting against mitochondrial dysfunction and axon development.

Could the RBM-26/MALS-1 regulatory axis be a potential therapeutic target for neurodevelopmental disorders, and what strategies could be explored to modulate this pathway?

The RBM-26/MALS-1 regulatory axis presents a promising therapeutic target for neurodevelopmental disorders due to its critical role in protecting against mitochondrial dysfunction and axon degeneration. Modulating this pathway could offer a novel approach to mitigating neurodevelopmental deficits associated with conditions like autism, intellectual disability, and ADHD. Strategies to target this axis could involve small molecule inhibitors or activators that regulate the interaction between RBM-26 and MALS-1, thereby modulating MALS-1 expression levels and mitochondrial function. Additionally, gene therapy approaches could be explored to restore proper RBM-26 function in individuals with autism-associated variants, potentially rescuing axonal defects and mitochondrial dysfunction. Furthermore, understanding the downstream effectors of the RBM-26/MALS-1 axis could reveal additional targets for therapeutic intervention, offering a comprehensive strategy to address neurodevelopmental disorders at the molecular level.