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Prolyl Isomerase Pin1 Expression in the Spinal Motor Neurons of Patients With Sporadic Amyotrophic Lateral Sclerosis
Haruhisa Kato1, Makiko Naito2, Tomoko Saito2
1Department of Neurology, Tokyo Medical University, Tokyo, Japan. h-kato@tokyo-med.ac.jp.
Background And Purpose:
Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. Selective deficiency of edited adenosine deaminase acting on RNA 2 (ADAR2), a key molecule in the acquisition of Ca2+ resistance in motor neurons, has been reported in sporadic ALS (sALS) spinal motor neurons. Since ADAR2 activity is positively regulated by prolyl isomerase Protein never in mitosis gene A interacting-1 (Pin1), a known phosphorylation-dependent peptidyl-prolyl cis/trans isomerase, we investigated Pin1 expression in spinal motor neurons in sALS.
Methods:
Specimens of the spinal cord were obtained from the lumbar region in eight sALS patients and age-matched five controls after postmortem examinations. The specimens were double stained with anti-Pin1 and anti-TAR DNA-binding protein of 43 kDa (TDP-43) antibodies, and examined under a fluorescence microscope.
Results:
This study analyzed 254 and 422 spinal motor neurons from 8 sALS patients and 5 control subjects, respectively. The frequency of motor neurons with high cytoplasmic Pin1 expression from the spinal cord did not differ significantly between sALS specimens without cytoplasmic TDP-43 inclusions and control specimens. However, in sALS specimens, neurons for which the Pin1 immunoluminescence intensity in the cytoplasm was at least twice that in the background were more common in specimens with cytoplasmic TDP-43 inclusions (p<0.05 in χ² test).
Conclusions:
In sALS, neurons with higher expression levels of Pin1 levels had more TDP-43 inclusions. Despite the feedback mechanism between Pin1 and ADAR2 being unclear, since Pin1 positively regulates ADAR2, our results suggest that higher Pin1 expression levels in motor neurons with TDP-43 pathology from sALS patients represent a compensatory mechanism.
Insights
In sporadic amyotrophic lateral sclerosis (sALS), higher levels of Protein never in mitosis gene A interacting-1 (Pin1) were found in motor neurons with TDP-43 inclusions, suggesting a compensatory mechanism for adenosine deaminase acting on RNA 2 (ADAR2) deficiency.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease.
- A selective deficiency of adenosine deaminase acting on RNA 2 (ADAR2) is observed in sporadic ALS (sALS) motor neurons.
- ADAR2 activity is positively regulated by prolyl isomerase Protein never in mitosis gene A interacting-1 (Pin1).
Purpose of the Study:
- To investigate Pin1 expression in spinal motor neurons in sALS.
- To explore the relationship between Pin1 and TDP-43 pathology in sALS.
Main Methods:
- Human spinal cord specimens from 8 sALS patients and 5 controls were analyzed.
- Double immunofluorescence staining for Pin1 and TDP-43 was performed.
- Pin1 expression levels in motor neurons were quantified using fluorescence microscopy.
Main Results:
- No significant difference in high cytoplasmic Pin1 expression was found between sALS without TDP-43 inclusions and controls.
- sALS neurons with cytoplasmic TDP-43 inclusions showed significantly higher Pin1 expression.
- Increased Pin1 immunofluorescence intensity was observed in sALS motor neurons with TDP-43 pathology.
Conclusions:
- Higher Pin1 expression correlates with TDP-43 inclusions in sALS motor neurons.
- Elevated Pin1 levels in TDP-43-positive neurons may represent a compensatory response.
- The precise feedback mechanism between Pin1 and ADAR2 in sALS remains to be elucidated.
