Coupling axonal mRNA transport and local translation to organelle maintenance and function

Abstract

Neuronal homeostasis requires the transport of various organelles to distal compartments and defects in this process lead to neurological disorders. Although several mechanisms for the delivery of organelles to axons and dendrites have been elucidated, exactly how this process is orchestrated is not well-understood. In this review, we discuss the recent literature supporting a novel paradigm - the co-shuttling of mRNAs with different membrane-bound organelles. This model postulates that the tethering of ribonucleoprotein complexes to endolysosomes and mitochondria allows for the spatiotemporal coupling of organelle transport and the delivery of transcripts to axons. Subcellular translation of these "hitchhiking" transcripts may thus provide a proximal source of proteins required for the maintenance and function of organelles in axons.

Figure 1

Tethering of mRNA and ribonucleoprotein granules to organelles. Motor proteins actively transport Rab5-positive early endosomes and Rab7- and LAMP1-positive late endosomes in axons. mRNP granules tethered to these organelles by various adaptor proteins transport mRNAs to distal compartments of neurons, facilitating in situ translation. Specifically, mRNPs that hitchhike on Rab5 vesicles are enriched in endosomal mRNAs, suggesting that local translation of these transcripts aids in the maintenance of endosomes in axons and dendrites. The FERRY complex is a specific adaptor protein tethering mRNAs to Rab5 containing early endosomes. It is composed of five subunits Fy1-Fy5; Fy2 holds this complex together by binding all other subunits. The coiled-coil domains of Fy2 contain various mRNA-interacting regions, which allows the FERRY complex to associate with mRNAs. Fy2 also associates directly with Rab5 to localize the FERRY complex specifically to early endosomes. Rab7-positive late endosomes, on the other hand, traffic mRNP granules via ANXA11. ANXA11 possess a membrane-binding domain that allows it to associate with LAMP1-positive vesicles, as well as an intrinsically-disordered domain that can bind mRNPs. Late endosomes also serve as hubs for precursor microRNAs. These unprocessed microRNAs can provide a pool of mature microRNAs to control the expression of mRNAs in distal compartments, and perhaps mRNAs that are tethered on late endosomes. In this manner, the transcripts, as well as their regulatory elements are co-transported on the same organelle. Moreover, the mTORC1 complex is localized and activated on the surface of late endosomes and lysosomes. Upon activation, mTORC1 initiates the translation of various mRNAs. Both Rab5-and Rab7-positive endosomes shuttle nuclear-encoded mitochondrial mRNAs, indicating that both these organelles are involved in the maintenance of mitochondria in distal neuronal compartments. Mitochondria also tether various mRNAs and mRNPs enriched for nuclear-encoded mitochondrial mRNAs. CLUH was identified to bind the outer mitochondrial membrane protein Tom20 and nuclear-encoded mitochondrial mRNAs. PINK1 kinase was also shown to bind mRNAs, linking these transcripts to mitochondria. Recently, SYNJ2BP was demonstrated to localize PINK1 mRNA to mitochondria. The local translation of PINK1 mRNA provides a steady pool of this protein, which is critical for mitophagy.