How mRNA transport affects neuronal health

Summary: Researchers have linked the survival and pathology of sensory neurons to the transport of mRNA in these cells.

They focused on the dynein protein complex, specifically the subunit Dynein Roadblock 1 (Dynlrb1), critical for neuronal survival. One intriguing finding was the role of FMRP in mRNA transport, which offers a more energy-efficient method than protein transport.

Dysfunctions in this system may be the key to understanding certain neuropathologies.

Key facts:

  1. Dynein, especially the Dynein Roadblock 1 (Dynlrb1) subunit, is essential for the survival of neurons and the transport of vital molecules within them.
  2. The research revealed that FMRP, linked to specific neurological and neurodegenerative diseases, plays a role in mRNA transport, potentially conserving energy for the neuron.
  3. Disturbances in Dynein Roadblock 1 can prevent the production of necessary proteins, threatening neuronal survival.

source: OIST

The Department of Molecular Neuroscience at the Okinawa Institute of Science and Technology (OIST) has made an important breakthrough by linking the survival and pathology of sensory neurons to the way information RNA (mRNA) is transported inside these cells.

This team of neuroscientists, composed of Ph.D. student Sara Emad El-Agamy, Dr. Laurent Guillaud and Prof. Marco Terenzio, collaborating with Prof. Keiko Kono from the OIST Membraneology Unit and Dr. Yibo Wu from the Riken Institute (now at the University of Geneva). The project was led by Sarah Emad El-Aghami, first author of the published study, as part of her Ph.D. work.

Finally, the team also found that removing Dynlrb1 caused FMRP to stop and accumulate in the cell bodies and axons of sensory neurons. Credit: Neuroscience News

“Neurons have perhaps the most extreme morphology among cells, as they can vary in shape and extend over great distances in large mammals. For example, the neurons that innervate a person’s leg can be more than a meter long: they may have their nucleus close to the spinal cord, but feel a tickling sensation in the legs or pain in the big toe,” explains Prof. Terenzio , who heads the OIST Department of Molecular Neuroscience.

Neurons have long projections called axons in which molecules such as proteins, RNA, and organelles move. This form of transport, from the center of the cell to the periphery and back, is the cellular equivalent of a network of highways and trucks.

The most important “trucks” responsible for driving “cargo” from the peripheral tips of neurons to their center are part of a large complex of proteins called dynein. Malfunctions in this transport system can lead to several types of neuropathologies.

Dynein is a large and complex protein composed of several subunits – or chains – that are graded by size.

“We investigated a part of the dynein complex called Dynein Roadblock 1, or Dynlrb1 for short. In previous experiments, we demonstrated that this dynein subunit is clearly essential for neuronal survival, but we needed to understand how it works,” says Prof. Terenzio.

The researchers wanted to test an idea: If we think of dynein as trucks that move cargo inside neurons, we can imagine that Dynlrb1 might affect the ability of the “dynein truck” to move, or its ability to carry cargo. To solve the mystery, the OIST team investigated the proteins that interact with this dynein subunit.

Among several interacting proteins, Sarah Emad El-Aghami focused on the fragile X messenger ribonucleoprotein 1 (FMRP), which is well known in the field of neurobiology because it is associated with a neurodevelopmental disorder (fragile X syndrome) and a neurodegenerative disease ( of fragile X-linked tremor/ataxia).

“The finding that FMRP is part of the dynein cargo is particularly interesting. FMRP granules are composed of two types of molecules, proteins and messenger RNA (mRNA). mRNA is the template used by ribosomes to make proteins.

“Since I am really interested in the RNA biology of axons, I did not want to miss the opportunity to go deeper into this topic,” explains Prof. Terenzio.

Axons were historically thought to lack RNA and protein synthesis machinery, with most of these processes thought to occur extremely close to the nuclei of neurons. However, relatively recent research has revealed that axons do contain a variety of RNA molecules.

Because synthesizing proteins in the center of the cell and then sending all those proteins to the tips of neurons like a large truckload would be a large investment of energy for long neurons, neurons deliver mRNA instead of proteins.

“A single mRNA can serve as a template for the production of several proteins. By transporting mRNA instead of the final proteins, cells can save a significant amount of energy, at least in theory,” explains Prof. Terenzio.

However, Sarah also found that FMRP spread from the periphery to the center.

“They are thought to normally be transported from the center of the cell to the periphery. The fact that we showed them being transported in the opposite direction was very surprising to us. This is a phenomenon that is just beginning to be described in the field, and I believe it will be important in the future,” says Prof. Terenzio.

Finally, the team also found that removing Dynlrb1 caused FMRP to stop and accumulate in the cell bodies and axons of sensory neurons. Because FMRP-bound mRNA is trapped and unable to undergo translation into proteins, the researchers hypothesize that Dynlrb1 plays a vital role in neuronal health.

In other words, damage to Dynlrb1 can hinder the production of essential proteins, endangering the survival of neurons.

“Our next research question is to understand which proteins cannot be produced when Dynlrb1 is dysfunctional or missing.” The data we obtained will help us understand what sustains neuronal survival and, as a consequence, neuronal death.

“This can be used to find new therapeutic approaches for neurodegenerative diseases,” concludes Prof. Terenzio.

About this genetics and neuroscience research news

Author: Tomomi Okubo
source: OIST
Contact: Tomomi Okubo – OIST
Image: Image credited to Neuroscience News

Original Research: Free access.
“Long-range transport and degradation of FMRP are mediated by Dynlrb1 in sensory neurons” by Sara Emad El-Agamy et al. Molecular and cellular proteomics


Long-range transport and degradation of FMRP are mediated by Dynlrb1 in sensory neurons

Fragile X messenger ribonucleoprotein 1 (FMRP) is a multifunctional RNA-binding protein implicated in human neurological and neurodegenerative disorders. FMRP mediates the localization and activity-dependent translation of its associated mRNAs by forming phase-separated condensates that are transported by microtubule-based motors in axons.

Axonal transport and localized mRNA translation are critical processes for the long-term survival of neurons and are closely related to the pathogenesis of neurological diseases. FMRP-mediated dynein axonal trafficking is still largely unexplored, but is likely to represent a key process underlying the spatiotemporal translational regulation of FMRP.

Here we show that dynein light chain block 1 (Dynlrb1), a subunit of the dynein complex, is a critical regulator of FMRP function. In sensory axons, FMRP associates with endolysosomal organelles, presumably via annexin A11, and is retrogradely transported by the dynein complex in a Dynlrb1-dependent manner.

Furthermore, silencing of Dynlrb1 induces accumulation of FMRP granules and represses the translation of microtubule-associated protein 1b, one of its major mRNA targets.

Our findings indicate that Dynlrb1 regulates FMRP function by controlling its transport and targeted degradation.

Leave a Comment

Your email address will not be published. Required fields are marked *