Related Experiment Video
Updated: Nov 3, 2025
Applying the RatWalker System for Gait Analysis in a Genetic Rat Model of Parkinson's Disease
Published on: January 18, 2021
Double p52Shc/p46Shc Rat Knockout Demonstrates Severe Gait Abnormalities Accompanied by Dilated Cardiomyopathy
Bradley Miller1, Tatiana Y Kostrominova2, Aron M Geurts3
1Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53266, USA.
Insights
The p46Shc protein isoform is crucial for regulating gait. Rats lacking p46Shc (and p52Shc) showed impaired locomotion and sciatic nerve abnormalities, suggesting a novel role for p46Shc signaling.
Area of Science:
- Cellular Biology
- Neuroscience
- Genetics
Background:
- The Shc adaptor protein family has three isoforms: p46Shc, p52Shc, and p66Shc, each with distinct cellular functions.
- The specific role of the p46Shc isoform in physiological processes remains largely uncharacterized.
Purpose of the Study:
- To investigate the functional significance of the p46Shc protein isoform.
- To elucidate the role of p46Shc in the regulation of locomotion and associated neurological pathways.
Main Methods:
- Development of unique rat mutants lacking both p52Shc and p46Shc isoforms (p52Shc/46Shc-KO).
- Histological analysis of skeletal and cardiac muscle tissues.
- Examination of sciatic nerve cross-sections, including axons and myelin sheaths.
Main Results:
- p52Shc/46Shc-KO rats exhibited severe gait abnormalities and functional deficits.
- Histological analysis revealed significant anomalies in sciatic nerve axons and myelin sheaths.
- Absence of skeletal muscle fiber atrophy, suggesting the gait impairment is not primarily muscular.
- Dilated cardiomyopathy was observed in some heart muscle fibers, indicated by a lack of dystrophin.
Conclusions:
- The deletion of p46Shc, not p52Shc alone, is likely responsible for the observed abnormal locomotion.
- Impaired gait in p52Shc/46Shc-KO rats may stem from altered sensory feedback due to sciatic nerve abnormalities.
- This study identifies a previously unrecognized role for p46Shc signaling in the regulation of gait and locomotion.
Abstract:
The ubiquitously expressed adaptor protein Shc exists in three isoforms p46Shc, p52Shc, and p66Shc, which execute distinctly different actions in cells. The role of p46Shc is insufficiently studied, and the purpose of this study was to further investigate its functional significance. We developed unique rat mutants lacking p52Shc and p46Shc isoforms (p52Shc/46Shc-KO) and carried out histological analysis of skeletal and cardiac muscle of parental and genetically modified rats with impaired gait. p52Shc/46Shc-KO rats demonstrate severe functional abnormalities associated with impaired gait. Our analysis of p52Shc/46Shc-KO rat axons and myelin sheets in cross-sections of the sciatic nerve revealed the presence of significant anomalies. Based on the lack of skeletal muscle fiber atrophy and the presence of sciatic nerve abnormalities, we suggest that the impaired gait in p52Shc/46Shc-KO rats might be due to the sensory feedback from active muscle to the brain locomotor centers. The lack of dystrophin in some heart muscle fibers reflects damage due to dilated cardiomyopathy. Since rats with only p52Shc knockout do not display the phenotype of p52Shc/p46Shc-KO, abnormal locomotion is likely to be caused by p46Shc deletion. Our data suggest a previously unknown role of 46Shc actions and signaling in regulation of gait.
