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Updated: Jun 12, 2026
In Vivo Electrophysiological Measurement of Compound Muscle Action Potential from the Forelimbs in Mouse Models of Motor Neuron Degeneration
Published on: June 15, 2018
Mutant HSPB8 causes motor neuron-specific neurite degeneration
Joy Irobi1, Leonardo Almeida-Souza, Bob Asselbergh
1Peripheral Neuropathy, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium.
Abstract:
Missense mutations (K141N and K141E) in the alpha-crystallin domain of the small heat shock protein HSPB8 (HSP22) cause distal hereditary motor neuropathy (distal HMN) or Charcot-Marie-Tooth neuropathy type 2L (CMT2L). The mechanism through which mutant HSPB8 leads to a specific motor neuron disease phenotype is currently unknown. To address this question, we compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures. In motor neurons, expression of both HSPB8 K141N and K141E mutations clearly resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Furthermore, expression of the K141E (and to a lesser extent, K141N) mutation also induced spheroids in the neurites. We did not detect any signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in motor neurons, these phenotypes were only very mildly present in sensory neurons and completely absent in cortical neurons. Also glial cells did not show an altered phenotype upon expression of mutant HSPB8. These findings show that despite the ubiquitous presence of HSPB8, only motor neurons appear to be affected by the K141N and K141E mutations which explain the predominant motor neuron phenotype in distal HMN and CMT2L.
Insights
Missense mutations in HSPB8 cause motor neuron disease by damaging neurites without cell death. Only motor neurons are affected, explaining the specific disease phenotype in distal HMN and CMT2L.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Missense mutations in the small heat shock protein HSPB8 (HSP22) alpha-crystallin domain lead to distal hereditary motor neuropathy (distal HMN) and Charcot-Marie-Tooth neuropathy type 2L (CMT2L).
- The precise mechanism by which mutant HSPB8 causes these specific motor neuron diseases remains unclear.
Purpose of the Study:
- To investigate the cellular mechanisms underlying mutant HSPB8-induced neurodegeneration.
- To determine the cell-type specificity of HSPB8 mutations' effects.
Main Methods:
- Primary neuronal and glial cell cultures were utilized to compare the effects of mutant HSPB8 expression.
- Expression of HSPB8 K141N and K141E mutations was analyzed in motor neurons, sensory neurons, cortical neurons, and glial cells.
Main Results:
- Expression of mutant HSPB8 (K141N and K141E) induced significant neurite degeneration in motor neurons, characterized by reduced neurite number and length.
- The K141E mutation, and to a lesser extent K141N, caused spheroid formation in motor neuron neurites.
- Neurite degeneration occurred without inducing apoptosis in motor neurons.
- Phenotypic alterations were minimal in sensory neurons and absent in cortical neurons and glial cells.
Conclusions:
- Mutant HSPB8 specifically affects motor neurons, leading to neurite degeneration without cell death.
- This cell-type specificity explains the predominant motor neuron involvement observed in distal HMN and CMT2L.
- HSPB8 mutations represent a targeted mechanism for motor neuron dysfunction in specific neuropathies.
