Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy
Abstract
:1. Introduction
2. An Overview of ALS
2.1. Clinical Characteristics of ALS
2.2. Motor Neuron Dysfunction in ALS
3. Clinical Research in Patients with ALS
3.1. Clinical Features of Sensory Neuron Dysfunction in ALS
3.2. Peripheral Nerve Abnormalities Observed in Patients with ALS
3.3. Pathological Alterations in Sensory Neurons in Patients with ALS
3.4. Abnormalities of the Somatosensory Cortex in Patients with ALS
4. Preclinical Research in ALS
4.1. Pathological Alterations in Sensory Neurons in Patients with ALS
4.2. Degeneration of DRG Neurons
4.3. Characteristic Abnormalities in Mesencephalic Trigeminal Neurons
4.4. Protein Aggregates and Mitochondrial Dysfunction
4.5. Glial Involvement
4.6. Excitotoxicity and Calcium Dysregulation
4.7. Oxidative Stress and Protein Homeostasis
4.8. Protein Changes in Sensory Neurons
4.9. Role of Cytoskeletal Dysregulation and Neuronal Transport
5. Targeting Proprioceptive Sensory Neurons as a Potential Therapy for ALS
5.1. Current ALS Drugs
5.2. Addressing DRG Neuron Abnormalities May Treat Motor Neuron Impairments in ALS
5.3. Potential for Gene Therapy Targeting TDP-43
5.4. Treatment Strategies for ALS Masticatory Abnormalities through the MesV
6. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Type of Sensory Neuron | Dysfunction | Number of Patients with ALS | References |
---|---|---|---|
Median nerve | Attenuation of postsynaptic high-frequency somatosensory evoked potential bursts in patients with ALS with a long duration of the disease. | 20 | [73] |
Sensory system | A total of 14.7% of patients with ALS have damaged sensory systems. | 150 | [62] |
Sensory cortex | Sensory cortex overexcitation is associated with shorter survival in patients with ALS. | 145 | [71] |
Intraepidermal nerve fibres | Decreased intraepidermal nerve fibres density with aggregation of TDP-43 in patients with ALS. | 18 | [74] |
Epidermal nerve fibres | Loss of intraepidermal nerve fibres. | 41 | [60] |
Intraepidermal nerve fibres | Increased axonal expansion rate and negative growth-related proteins in intraepidermal nerve fibres. | 32 | [58] |
Intraepidermal nerve fibres | In 85% of patients with ALS, quantitative sensory testing showed abnormal thermal pain thresholds and skin biopsies showed decreased intraepidermal nerve fibre density. | 24 | [75] |
Ascending sensory fibres | Anatomical damage to ascending sensory fibres in 60% of patients with solitary ALS. | 21 | [76] |
Leg sensory nerve | A total of 27% of patients with ALS had abnormal action potential. Amplitude, and 91% had pathological abnormalities of the leg sensory nerve. | 103 | [56] |
Sensory neuron in sural | Sensory neuropathy and axonal degeneration. | 5 | [77] |
Median, radial, and sural nerves | Asymptomatic decline in sensory nerve function. | 19 | [67] |
Sensory nerves | Early axonal atrophy, increased remyelination, and predominance of smaller fibre diameters. | [78] |
Animal Model | Animals | Characteristics of the Model | References |
---|---|---|---|
SOD1G93A | Mouse | Marked muscle weakness is observed at 15 weeks of age in SOD1G93A transgenic mice with familial ALS | [33] |
dSOD1G85R | Drosophila | SOD1G85R knock-in model shows severe motor deficits with apparent degeneration of motor neurons, providing a better understanding of the contribution of multiple cell types in ALS | [72] |
C9orf72 ALS | Drosophila | Transgenic Drosophila model overexpressing human TDP-43 shows reduced lifespan, reduced motor activity, increased morphological defects in motor neurons, a loss of neurons, and axonal damage | [88] |
TDP-43A315T | Mouse | A315T mutant TDP-43 transgenic mouse model with marked early-onset progressive neurodegeneration resulting in reduced motor performance, spatial memory and deinhibition, and reduced grip strength due to muscle atrophy | [84] |
TDP-43 (TBPH) | Drosophila | Transgenic fly that exhibits an adult locomotor defect and shares many features with human proteins | [89] |
Type of Sensory Neuron | Dysfunction | Type of Animals | Genes | References |
---|---|---|---|---|
MesV | Firing abnormality | Mouse | SOD1 G93A | [36] |
DRG | Decrease in SGNF density | Mouse | SOD1 G93A | [33] |
C4da | TDP-43 accumulation in the cytoplasm via calcium-calpain-A-importin α3 pathway | Drosophila | C9orf72 ALS | [88] |
DRG | SOD1 accumulation in SGCs | Mouse | SOD1 G93A | [8] |
MesV | Firing abnormality with sodium channel dysfunction | Mouse | SOD1 G93A | [35] |
Non-motor neuron | Neurotrophic BMP pathway | Drosophila | dSOD1G85R | [72] |
DRG | Shorter and less complex neurites | Mouse | TDP43 A315TSOD1 G93A | [84] |
Long-projection sensory neurons | Defects in MAM signalling | Mouse | TDP43 A315T | [93] |
Olfactory bulb and retina | Neuronal vacuolisation in olfaction and vision pathways | Mouse | SOD1 G93A | [87] |
DRG | Accumulation of a peripherin splice variant | Mouse | SOD1 G93A | [34] |
DRG | Accumulation of misfolded protein | Mouse | dSOD1G85R | [94] |
Ia and II proprioceptive nerve | Early disturbances in muscle spindles before motor neuron symptoms | Mouse | TDP43 A315T SOD1 G93A | [95] |
C4da | Localised accumulation, predominantly of TDP-43 | Drosophila | TDP-43 (TBPH) | [89] |
DRG | Mitochondrial abnormalities | Mouse | SOD1 G93A | [90] |
DRG | Reduction of high-voltage-activated Ca2+ current | Mouse | ICR mice injected with sera from patients with ALS | [91] |
Genes | Type of Sensory Neuron | Function | References |
---|---|---|---|
SOD1 | DRG | Encodes an itinerant enzyme that catalyses the conversion of superoxide to hydrogen peroxide and dioxygen. | [117] |
KIF1A | DRG | Encodes the kinesin 3 motor that transports presynaptic vesicle precursors and dense core vesicles. | [123] |
TARDBP | DRG | Mainly localised in the nucleus and regulates RNA processing. | [122] |
FUS | VNC | RNA-binding protein. | [104] |
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Seki, S.; Kitaoka, Y.; Kawata, S.; Nishiura, A.; Uchihashi, T.; Hiraoka, S.-i.; Yokota, Y.; Isomura, E.T.; Kogo, M.; Tanaka, S. Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy. Biomedicines 2023, 11, 2967. https://doi.org/10.3390/biomedicines11112967
Seki S, Kitaoka Y, Kawata S, Nishiura A, Uchihashi T, Hiraoka S-i, Yokota Y, Isomura ET, Kogo M, Tanaka S. Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy. Biomedicines. 2023; 11(11):2967. https://doi.org/10.3390/biomedicines11112967
Chicago/Turabian StyleSeki, Soju, Yoshihiro Kitaoka, Sou Kawata, Akira Nishiura, Toshihiro Uchihashi, Shin-ichiro Hiraoka, Yusuke Yokota, Emiko Tanaka Isomura, Mikihiko Kogo, and Susumu Tanaka. 2023. "Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy" Biomedicines 11, no. 11: 2967. https://doi.org/10.3390/biomedicines11112967
APA StyleSeki, S., Kitaoka, Y., Kawata, S., Nishiura, A., Uchihashi, T., Hiraoka, S.-i., Yokota, Y., Isomura, E. T., Kogo, M., & Tanaka, S. (2023). Characteristics of Sensory Neuron Dysfunction in Amyotrophic Lateral Sclerosis (ALS): Potential for ALS Therapy. Biomedicines, 11(11), 2967. https://doi.org/10.3390/biomedicines11112967