Towards a cure for NARS disease

Pathogenic alleles in human asparaginyl-tRNA synthetase (NARS1) cause heterogeneous genetic disorders collectively known as NARS1 diseases. NARS1 disease is an early onset disease, and few children reach adulthood. No NARS1 specific therapies are available, and treatments remain supportive. The molecular and cellular consequences of most pathogenic NARS1 alleles remain unknown. We will investigate NARS1 mutations using biochemical analyses, a humanized yeast model system, and human cell models of NARS1 disease. Results from these systems will reveal how NARS1 mutations contribute to disease, thus enabling exploration of potential treatment options for NARS1 patients. For other diseases related to aminoacyl-tRNA synthetases, amino acid supplementation has shown success in patients, and tRNA therapy was successful in mouse and humanized yeast models. Additionally, small molecule therapeutics have shown promise in alleviating cellular consequences associated with NARS1 alleles. We anticipate NARS1 alleles will require allele-specific interventions. Using humanized yeast, I will test whether amino acid supplementation, tRNA supplementation, or small molecule therapeutics can alleviate phenotypes associated with disease. By processing patient data, this project will support CHRI/LHSC physicians that frequently diagnose and treat aminoacyl-tRNA synthetase diseases. By identifying priority alleles to study, the results of this research will improve patient outcomes.

Faculty Supervisor:

Ilka Heinemann

Student:

Partner:

London Health Sciences Centre

Discipline:

Life Sciences

Sector:

Health and Related Sciences & Technology

University:

The University of Western Ontario

Program: