*Result*: Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis.

Title:
Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis.
Authors:
Tra NT; Department of Functional Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan., Kiryu-Seo S; Department of Functional Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan., Kida H; Department of Functional Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan., Wakatsuki K; Department of Functional Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan., Tashiro Y; Department of Neurology, Kyoto University, Graduate School of Medicine, Kyoto 606-8507, Japan., Tsutsumi M; Biophotonics Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.; Research Division of Biophotonics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki 444-8787, Japan., Ataka M; Biophotonics Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.; Research Division of Biophotonics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki 444-8787, Japan., Iguchi Y; Department of Neurology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan., Nemoto T; Biophotonics Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.; Research Division of Biophotonics, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki 444-8787, Japan., Takahashi R; Department of Neurology, Kyoto University, Graduate School of Medicine, Kyoto 606-8507, Japan.; Research Administration Center, Kyoto University (KURA), Kyoto 606-8507, Japan., Katsuno M; Department of Neurology, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan., Kiyama H; Department of Functional Anatomy and Neuroscience, Nagoya University, Graduate School of Medicine, Nagoya 466-8550, Japan.; Shijonawate Gakuen University, Osaka 547-0001, Japan.
Source:
Brain : a journal of neurology [Brain] 2025 Nov 04; Vol. 148 (11), pp. 4030-4044.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
Imprint Name(s):
Publication: Oxford : Oxford University Press
Original Publication: London.
MeSH Terms:
Amyotrophic Lateral Sclerosis*/pathology , Amyotrophic Lateral Sclerosis*/metabolism , Amyotrophic Lateral Sclerosis*/genetics , Sensory Receptor Cells*/pathology , Sensory Receptor Cells*/metabolism , Axon Initial Segment*/pathology , Axons*/pathology, Ganglia, Spinal/pathology ; Ganglia, Spinal/metabolism ; Motor Neurons/pathology ; Motor Neurons/metabolism ; Activating Transcription Factor 3/metabolism ; Activating Transcription Factor 3/genetics ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Endopeptidase Complex/genetics ; Mitochondria/metabolism ; Mitochondria/pathology ; Animals ; Mice ; Disease Models, Animal ; Mice, Transgenic ; Mice, Inbred C57BL
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Grant Information:
21K19310 Japan Society for the Promotion of Science; 23H04229 Japan Society for the Promotion of Science; 24K02350 Japan Society for the Promotion of Science; 23K24695 Japan Society for the Promotion of Science; JSPS; 21K19310 KAKENHI; 23H04229 KAKENHI; 24K02350 KAKENHI; 23K24695 KAKENHI
Contributed Indexing:
Keywords: Rpt3 (Pmsc4); amyotrophic lateral sclerosis; axonal transport; neurodegeneration; neuronal injury; proteostasis
Substance Nomenclature:
0 (Activating Transcription Factor 3)
0 (Atf3 protein, mouse)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
Entry Date(s):
Date Created: 20250707 Date Completed: 20251105 Latest Revision: 20251107
Update Code:
20260130
PubMed Central ID:
PMC12588706
DOI:
10.1093/brain/awaf182
PMID:
40622763
Database:
MEDLINE

*Further Information*

*Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Proteasome dysfunction in ALS is considered to cause the accumulation of protein aggregates, which leads to motor neuron degeneration; however, the resilience of motor neurons to ALS pathology might be impaired long before the appearance of protein aggregates. Intriguingly, sensory dorsal root ganglion (DRG) neurons are not susceptible to ALS pathology despite their processes coexisting with axons of motor neurons in the same spinal nerves. Both DRG neurons and motor neurons in ALS model mice express activating transcription factor 3 (ATF3), a well-known marker of nerve injury and disease progression, suggesting that both types of neurons respond to ALS pathology. However, it remains unknown why only DRG neurons are resilient to ALS pathological damage. To address this issue, we used a nerve injury model in combination with unique injury-induced genetically engineered mice, in which genetic control with an Atf3 regulatory element enables proteasome ablation and mitochondrial visualization specifically in damaged neurons. Using the strategy, we found that DRG neurons are resistant to damage in proteasome-deficient conditions, whereas spinal motor neurons degenerate in the same conditions. This might be because DRG neurons lack the typical axon initial segment (AIS), which normally exists in mature neurons and acts as a gate for the selective transport of cargo to axons. The absence of a typical AIS in DRG neurons facilitated increased entry of mitochondria into the axon upon injury, with or without proteasome function. In contrast, damaged motor neurons lacking the proteasome failed to disassemble the AIS, which prevented increased mitochondrial influx into axons and led to energy depletion and degeneration. In the absence of the AIS, DRG neurons in the ALS mouse model are able to deliver sufficient mitochondria into the axon to prevent pathological damage. However, impaired proteasome function in ALS motor neurons results in retention of the AIS gate and failure of mitochondrial transport to axons. This is a possible reason why DRG neurons have greater resilience to ALS pathological damage compared with spinal motor neurons. Collectively, this study opens new directions for the understanding of neurodegenerative diseases at early stages of disturbed protein homeostasis.
(© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)*