Expression of Heat-Shock Proteins in the Presence of Oxidative Stress in the Sod1-G93a Amyotrophic Lateral Sclerosis Mouse Model
Bernhardt, Kamren D
MetadataShow full item record
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes death of motoneurons, resulting in paralysis, dysphagia, respiratory distress and ultimately death. The precise causes of this fatal disease are unknown, but the mechanisms contributing to motoneuron death have been researched extensively. Oxidative stress has been established as one mechanism of motoneuron death associated with ALS. Protein misfolding is a cellular dysfunction that occurs more commonly in increased levels of oxidative stress. Large concentrations of misfolded proteins interfere with neuron signaling and trigger apoptotic pathways leading to degeneration. Heat Shock Proteins (HSPs) are chaperones that assist in proper protein folding. The purpose of this research is to determine where and to what extent HSP levels are not being properly upregulated to counter the negative effects of oxidative stress associated with ALS, to determine their corresponding impact on cellular degeneration, and to assess the susceptibility of spinal motoneurons and muscle to oxidative stress. We perform a meta-analysis of HSPs from 11 peer-reviewed experimental journal articles assessing HSP levels in the SOD1-G93A transgenic ALS mouse model. Aggregated analysis of HSP levels in SOD1-G93A ALS transgenic mice revealed that HSPs are downregulated in the limbs at most stages of the disease, and are significantly lower than HSP levels in the spine. In contrast, HSP levels in the spine are significantly upregulated in comparison to wild type or non-ALS mice. Since HSPs combat protein misfolding, the compensatory upregulation of HSPs in the ALS pathology is insufficient to counteract oxidative stress. Our results suggest that the muscle cells are more vulnerable to oxidative-related degradation than spinal motoneurons. In summary, HSPs as a clinical therapeutic strategy delivered to the muscle and/or spine could be particularly helpful in early stages of ALS, where their effect in delaying oxidative stress induced cellular death is maximal.