Selective Inhibition of Pathological Mitochondrial Fission to Improve Mitochondrial Function and Inhibit Neurodegeneration and Neuroinflammation in ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the death of upper and lower neurons in the brain that control our muscles (called motor neurons). ALS is manifested clinically by progressive muscle wasting and paralysis, and individuals with ALS most commonly die of respiratory failure or pneumonia within 35 years of initial diagnosis. There is no cure for ALS but two drugs, riluzole and edaravone, are approved to treat ALS by modestly slowing the progress of disease. Given this, there is a strong need to develop new and improved treatment strategies for the ALS patient community. However, the primary cause of ALS remains unclear.We recently demonstrated a critical role for mitochondrial dysfunction in general and excessive mitochondrial fragmentation as a major cause for the pathology; we showed that two proteins (Drp1 and Fis1) interact to initiate excessive mitochondrial fragmentation, and have designed a peptide inhibitor, P110 peptide, that blocks Drp1/Fis1 interaction in mitochondria and is effective in ALS patient-derived cells and in an ALS mouse model. In the first year of the proposal, we identified and evaluated novel small molecule mimetics of P110, SC9, as potential therapeutic candidates for ALS treatment. Since dysfunctional mitochondria have been observed in a broad range of ALS patients,we anticipate treatment with a fission inhibitor will provide some benefit to all patients, regardless of the mechanism underlying disease development. In the coming year the pharmacological properties of SC9 and analogues will be evaluated.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2023
- Accession Number
- AD1203902
Entities
People
- Daria Mochly-rosen
- Suman Pokhrel
Organizations
- Stanford University