Messenger RNA transport on lysosomal vesicles maintains axonal mitochondrial homeostasis and prevents axonal degeneration

This study utilized induced pluripotent stem cell (iPSC)-derived neurons to investigate the critical role of lysosome-related vesicles in axonal mRNA transport and mitochondrial homeostasis maintenance. By knocking out BORC subunits (borcs5 or borcs7) to block the entry of lysosome-related vesicles into axons, researchers found that this led to a significant reduction in a group of mRNAs primarily encoding ribosomal and mitochondrial/oxidative phosphorylation proteins in the axons.

RNA sequencing results showed that in the axons of wild-type neurons, mRNAs were primarily enriched in genes encoding ribosomal and mitochondrial/oxidative phosphorylation proteins. However, BORC knockout significantly reduced the abundance of these mRNAs in the axons. Pathway analysis revealed that these reduced mRNAs are associated with common neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, and amyotrophic lateral sclerosis (ALS).

Using RNA visualization techniques, researchers directly observed that the axonal transport of rps7 and rps27a mRNAs encoding ribosomal proteins was disrupted in BORC knockout cells. Furthermore, the lack of these mRNAs led to decreased translation of mitochondrial proteins, abnormal mitochondrial morphology, decreased membrane potential, increased reactive oxygen species, and induced axonal swelling and accumulation of autophagosomes.

In summary, this study elucidated a new mechanism whereby lysosome-related vesicles “transport” certain mRNAs for long-distance axonal transport and revealed the importance of this process in maintaining axonal mitochondrial and translational homeostasis. BORC deficiency-induced axonal mRNA reduction and mitochondrial dysfunction may be potential pathological mechanisms leading to neurodevelopmental defects or neurodegenerative diseases.

The study’s key highlights are:

1. Innovatively utilized iPSC neurons and microfluidic culture systems to obtain sufficient purified axonal samples for whole transcriptome sequencing.
2. Identified a large number of mRNAs dependent on lysosome-related vesicles for long-distance axonal transport, primarily enriched in translation and mitochondrial function-related genes.
3. Directly observed and quantified the BORC-mediated lysosomal transport-dependent axonal motility of mRNAs encoding ribosomal proteins.
4. Elucidated the potential mechanism by which BORC deficiency leads to impaired axonal translation and mitochondrial function.
5. Found that the axonal mRNA profile associated with BORC deficiency is related to multiple common neurodegenerative diseases, revealing potential shared pathological pathways.

This study provides new insights into the mechanisms by which long-distance axonal mRNA transport regulates axonal homeostasis and function and offers new perspectives for understanding the pathology of neurodevelopmental defects and neurodegenerative diseases caused by BORC deficiency.