Life science
Medical & healthcare, Drug discovery

Development of therapeutic agents for amyotrophic lateralsclerosis by improving ribosome function
Department of Neurotherapeutics, Graduate School of Medicine
Professor Seiichi Nagano
Researchmap https://researchmap.jp/read0106301

Life science

Abstract
Amyotrophic lateral sclerosis (ALS) is a neurological disorderthat causes muscle weakness and atrophy due to motor neuronaldegeneration. In most ALS cases, TDP-43 is abnormally deposited
mainly in neurons, but it was unclear how TDP-43 functions in neurons and how the deposition of TDP-43 causes ALS.
TDP-43 has been shown to bind to a large number of mRNAsand act on their intracellular maturation and transport. We focusedon axons, which are the protruding structures of neurons, andidentified mRNAs encoding ribosomal protein (ribosome proteinmRNAs) as targets transported to axons by TDP-43. TDP-43 transports ribosomal protein mRNAs to axons to maintain the amount ofribosomal proteins produced in axons, which in turn maintains thenumber of ribosomes to translate various proteins in axons, whichleads to maintaining the morphology and function of neurons (Figs.
1 and 2).

▍ Significance of the research and Future perspective
In the future, it will be possible to develop a fundamental therapeutic method for ALS based on a new mechanism of action bytransporting ribosomal protein mRNAs to axons, translating it there,and identifying drugs that increase the function of ribosomes in axons.

▍ Background & Results
We established a method for collecting only the axon portion
from cultured neurons, and used that method to search for mRNAs
that are reduced in the axons of neurons in which TDP-43 was reduced by the microarray method. As a result, multiple ribosomal
protein mRNAs were identified as a group of genes that were significantly reduced.
Ribosome proteins are proteins that constitute ribosome, which
is an intracellular apparatus essential for translating proteins frommRNAs, and has a great influence on the translation efficiency ofthe entire protein by the ribosome. Analysis using cultured neurons
revealed that ribosomal protein mRNAs co-localize with TDP-43 ina granular manner, ribosomal protein mRNAs and TDP-43 bind toeach other, and the transport of granules containing ribosomal protein mRNAs to the axons was reduced due to a decrease in TDP43. It was also found that ribosomal protein mRNAs transported toaxons are translated into ribosomal proteins in axons by stimulationof neurons, and plays an important role in maintaining the translation function of ribosomes.
When TDP-43 is decreased in cultured neurons and neurons inmouse brains, axon elongation gradually deteriorates, but wheneach ribosomal protein mRNA is overexpressed at the same time,axon elongation was confirmed to improve (Fig. 2). Furthermore,when the motor neurons of the brain tissue of ALS patients withabnormal TDP-43 deposition were examined, it was found that multiple ribosomal protein mRNAs were decreased.
From the above, TDP-43 has the function of transporting ribosomal protein mRNAs to the axon in neurons, thereby supplying theFig. 1. Model
ofthe
ALS
pathogenesis
ribosomal
proteins inaxon
to maintain the translation function
byby
theTDP-43
ribosome.deposition
It was also clarified that the synthesis of various
proteins in the axons was impaired and the elongation of the axons
was inhibited, which were presumed to be associated with the onset of ALS (Fig. 1).

Fig. 1. Model of ALS pathogenesis
by TDP-43 deposition

Fig. 1. Model of ALS pathogenesis by TDP-43 deposition

Fig. 2. Protective effects of Rp on axon
outgrowth deficit by TDP-43 KD

Fig. 2. Protective effects of Rp on axon outgrowth deficit by TDP-43 KD

P a t e n t Japanese Patent Application No. 2016-087320，Japanese Unexamined Patent Publication No. 2017-197443
Nagano, Seiichi; Jinno, Junki; Abdelhamid, Rehab F. et al. TDP-43 transports ribosomal protein mRNA to regulate axonal local translation in neuronal
Tr e a t i s eaxons. Acta Neuropathol. 2020; 140(5): 695-713. doi: 10.1007/s00401-020-02205-y
URL
K e y w o r d amyotrophic lateral sclerosis, TDP-43, mRNA, axonal transport, ribosomal protein