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Updated: Feb 25, 2026
Gait Analysis of Age-dependent Motor Impairments in Mice with Neurodegeneration
Published on: June 18, 2018
Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7
Tokiwa Yamasaki1, Norie Deki-Arima1, Asahito Kaneko2
1Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Abstract:
c-Jun N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase family and controls various physiological processes including apoptosis. A specific upstream activator of JNKs is the mitogen-activated protein kinase kinase 7 (MKK7). It has been reported that MKK7-JNK signaling plays an important regulatory role in neural development, however, post-developmental functions in the nervous system have not been elucidated. In this study, we generated neuron-specific Mkk7 knockout mice (MKK7 cKO), which impaired constitutive activation of JNK in the nervous system. MKK7 cKO mice displayed impaired circadian behavioral rhythms and decreased locomotor activity. MKK7 cKO mice at 8 months showed motor dysfunctions such as weakness of hind-limb and gait abnormality in an age-dependent manner. Axonal degeneration in the spinal cord and muscle atrophy were also observed, along with accumulation of the axonal transport proteins JNK-interacting protein 1 and amyloid beta precursor protein in the brains and spinal cords of MKK7 cKO mice. Thus, the MKK7-JNK signaling pathway plays important roles in regulating circadian rhythms and neuronal maintenance in the adult nervous system.
Insights
The MKK7-JNK pathway is crucial for adult nervous system function. Neuron-specific knockout mice show circadian rhythm, motor, and neuronal maintenance deficits, highlighting MKK7
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The c-Jun N-terminal kinase (JNK) pathway, activated by mitogen-activated protein kinase kinase 7 (MKK7), is vital for cellular processes like apoptosis.
- While MKK7-JNK signaling is known for its role in neural development, its functions in the adult nervous system remain largely uncharacterized.
Purpose of the Study:
- To investigate the post-developmental functions of the MKK7-JNK signaling pathway in the adult mammalian nervous system.
- To elucidate the role of MKK7 in maintaining circadian rhythms, locomotor activity, and motor function.
Main Methods:
- Generation of neuron-specific Mkk7 knockout mice (MKK7 cKO) to impair constitutive JNK activation in the nervous system.
- Behavioral analysis of MKK7 cKO mice, including assessment of circadian rhythms, locomotor activity, and motor function (gait, hind-limb strength).
- Histological examination of spinal cord and brain tissues to identify axonal degeneration and protein accumulation.
Main Results:
- MKK7 cKO mice exhibited disrupted circadian behavioral rhythms and reduced locomotor activity.
- Progressive motor impairments, including hind-limb weakness and gait abnormalities, were observed in MKK7 cKO mice with age.
- Axonal degeneration in the spinal cord, muscle atrophy, and accumulation of axonal transport proteins (JIP1, APP) were evident in MKK7 cKO mice.
Conclusions:
- The MKK7-JNK signaling pathway is essential for regulating circadian rhythms in the adult nervous system.
- MKK7 plays a critical role in the maintenance of neuronal integrity and function in adult mammals.
- Disruption of MKK7-JNK signaling leads to age-dependent neurodegenerative phenotypes and motor dysfunction.
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