Glial activation and TNFR-I upregulation precedes motor dysfunction in the spinal cord of mnd mice
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Published on: November 4, 2017
Tiziana Mennini1, Paolo Bigini, Alfredo Cagnotto
1Department Molecular Biochemistry and Pharmacology, Mario Negri Institute for Pharmacological Research, Via Eritrea, 62, 20157, Milan, Italy. tiziana@marionegri.it
Abstract:
Mice homozygous for the spontaneous motor neuron degeneration mutation (mnd) show at the age of 8 months a marked impairment of the motor function and accumulation of lipofuscin granules in the cytoplasm of almost all neurons of the central nervous system. We previously reported a significant increase in GFAP protein levels in the lumbar spinal cord homogenates by western blot analysis and upregulation of TNF, a proinflammatory cytokine, in the motor neurons of lumbar spinal cord of mnd mice, already in a presymptomatic stage (4 months of age). In the present study, using immunohistochemical analysis, we performed a time course in mnd mice (1, 4 and 9 months of age) evaluating the expression and the distribution of astroglial and microglial cells and the expression of both TNF receptors, TNFR-I and TNFR-II. We observed a marked increase in astroglial and microglial cells and in TNFR-I immunoreactivity already at the 4th month. Since motor neuron dysfunction occurs in mnd mice in the absence of evident loss of spinal motor neurons, the present results indicate that the activation of microglial cells and astrocytes is independent from neuronal degeneration. The role of TNF and TNFR-I on motor neurons is still to be demonstrated.
Insights
Motor neuron degeneration in mnd mice involves early glial cell activation and increased TNF receptor-I, independent of neuronal loss. This suggests glial cells play a key role in motor neuron dysfunction.
Area of Science:
- Neuroscience
- Neurodegeneration
- Immunology
Background:
- Mice with the motor neuron degeneration (mnd) mutation exhibit motor dysfunction and lipofuscin accumulation by 8 months.
- Previous studies noted increased GFAP and TNF in presymptomatic mnd mice.
Purpose of the Study:
- To investigate the temporal expression and distribution of glial cells (astrocytes and microglia) and TNF receptors (TNFR-I, TNFR-II) in mnd mice.
- To determine if glial activation precedes or follows neuronal degeneration.
Main Methods:
- Immunohistochemical analysis was performed on mnd mice at 1, 4, and 9 months of age.
- Evaluated glial cell populations and TNF receptor expression.
Main Results:
- A significant increase in astroglial and microglial cells was observed by 4 months of age.
- Increased TNFR-I immunoreactivity was also evident at 4 months.
- Glial cell activation occurred independently of apparent motor neuron loss.
Conclusions:
- Glial cell activation (microglia and astrocytes) and TNFR-I upregulation are early events in mnd mice.
- These changes are independent of overt neuronal degeneration, suggesting a primary role in motor neuron dysfunction.
- The specific role of TNF and TNFR-I in motor neuron pathology requires further investigation.
