RNA transport and local translation in neurodevelopmental and neurodegenerative disease

Abstract

Neurons decentralize protein synthesis from the cell body to support the active metabolism of remote dendritic and axonal compartments. The neuronal RNA transport apparatus, composed of cis-acting RNA regulatory elements, neuronal transport granule proteins, and motor adaptor complexes, drives the long-distance RNA trafficking required for local protein synthesis. Over the past decade, advances in human genetics, subcellular biochemistry, and high-resolution imaging have implicated each member of the apparatus in several neurodegenerative diseases, establishing failed RNA transport and associated processes as a unifying pathomechanism. In this review, we deconstruct the RNA transport apparatus, exploring each constituent's role in RNA localization and illuminating their unique contributions to neurodegeneration.

Fig. 1 |. The RNA transport apparatus in health and disease.

RNA transport is a ubiquitous process in healthy neurons that is driven by a multipartite apparatus. Acting together, the components of the RTA enable local protein synthesis in axons and dendrites, supporting active metabolism at these remote sites. Genetic and age-related dysfunction of RNA regulatory elements, transport granule proteins or motor adaptor complexes often leads to degenerative disease by impairing local protein synthesis.

Fig. 2 |. Neuronal cis-acting RNA regulatory element structure, function and dysfunction.

a, Compared to non-neuronal cells, the 3′ UTR regions of neuronal mRNAs, which often encode information for transcript localization, are substantially longer and contain more secondary structure. Within neurons, mRNAs that localize to neuritis are longer, richer in secondary structure and have a longer half-life than their counterparts in the soma. The extended length of neuritic transcripts results from repeated, as well as unique, sequence motifs and secondary structures. b, Secondary structures and sequence motifs in different parts of the mRNA transcript encode localization to different parts of a neurite. In this example, information in the coding sequence drives localization to the primary branch of the neurite, whereas the 5′ and 3′ UTRs are necessary for specification to secondary and tertiary branches, respectively. c, Dysfunction in RNA regulatory regions contributes to neuronal dysfunction through direct aggregation, seeding RNA/protein aggregates and preventing the accurate routing (UTR disruption) of transcripts to the regions that require them.

Fig. 3 |. Neuronal transport granule properties.

a, The major known components of neuronal transport granules are RNA, RBPs and ribosomal subunits/ assembly factors. Transport granules shuttle freely in distal neurites. b, Transient, low-affinity and multivalent interactions drive protein condensation, which is the organizing principle of transport granule assembly. These membrane-less organelles exhibit dynamic exchange with the cytoplasm, enabling regulated RNA and protein flux. c, RNA–protein co-acervation, or co-assembly through LLPS, is required for transport granule formation. SMN protein facilitates transport granule assembly by promoting the interactions between RBPs and their RNA targets. The absence of SMN protein in SMA results in fewer successfully formed granules, less distal RNA delivery and ultimately motor neuron degeneration. d, Dynamic assembly and disassembly of transport granules is essential for proximal packaging and distal release of RNA cargo. Hyper-assembly and solidiffcation of granules, caused by mutations in several ALS/FTD-related proteins (for example, FUS and TDP-43), result in impaired RNA delivery to distal sites. This deficit causes neuritic dysfunction, leading to neurodegenerative disease. e, Transport granules enable site-specific translation by limiting translation before arrival and tuning translation at the destination site to local needs. FMRP normally regulates this balance, and so its loss leads to uncontrolled protein synthesis, as well as malformed and dysfunctional neuritic structures. These cellular defects characterize FXS.

Fig. 4 |. Motor adaptors for RNA transport.

a, KLC and BICD2 each bind RBPs and molecular motors (kinesin or dynein, respectively) simultaneously, enabling transport granule trafficking. b, The LE/Lys is a recently characterized vesicular adaptor between transport granules and microtubule-based motors. This system requires the secondary adaptors Rab7 (between the motor complex and the LE/Lys) and ANXA11 (between the LE/Lys and transport granule). ANXA11 has unique biophysical characteristics that enable its tethering function, as its granule-interacting N-terminus undergoes LLPS, and its LE/Lys-interacting C-terminus binds LE/Lys-specific phospholipids. c, Familial neurodegenerative diseases reveal mutations in motor adaptors for RNA transport, underscoring the critical role for adaptors in RNA transport and long-term neuronal health. These diseases affect long motor neurons, which are exceptionally dependent on robust axonal trafficking mechanisms.

Fig. 5 |. The RNA transport apparatus and local metabolism.

a, Upon arrival at the site where RNA is to be released for protein synthesis (mRNA) or translational inhibition (miRNA), the granule must undergo partial or full de-condensation. Membrane receptors, in response to neurotransmitter stimulation, can activate signaling pathways that trigger RBP post-translational modifications and cause granule dispersal. Molecular chaperones contained within the granule, which control biophysical changes involved in nuclear transit, can also disperse granules distally. b, RNA-modifying machinery, such as nucleases (light gray, dark gray and black) and polymerases (Gld2), are active in neurites. In response to various chemical and electrical stimuli, this machinery can precisely tune the translational status of a particular mRNA to local needs. c, Neuritic ribosomes can be released from membrane receptor (transmembrane receptor DCC) scaffolds by local stimulation, trafficked into neurites within transport granules or hitchhiked on the surface of LE/Lys. Within neurites, ribosomes undergo local remodeling to enable location-specific translation, participate in the late stages of RNA transport and undertake predominantly monosomal translation of mRNAs. d, Neurons employ two main proteolytic systems to maintain distal proteostasis. The proteasome, which processes small degradative cargoes, is recruited to and active within dendrites. The autophagy machinery (LE/Lys and autophagosomes), which typically handles larger cargoes, such as large protein assemblies or whole organelles, has primarily been observed within axons. e, Neurite outgrowth, maturation and maintenance over time are dependent upon the continual replenishment of new protein and the clearance of dysfunctional organelles and protein aggregates. As neurons age, both local translation and local turnover decrease, resulting in decreased overall function. Neurodegenerative diseases accelerate and intensify these changes (less local translation, more aggregates and UTR fragment accumulation), leading to drastic functional impairments.