A substantial number of drugs found to alleviate symptoms of motor neuron diseases (MNDs) in animal models have failed in clinical trials. While the reasons for this are not clear, modeling disease with cell types from affected patients may yield novel mechanisms and pathways, setting the stage for the discovery of new drugs targeting MNDs. Therefore, our lab focuses on the investigation of the molecular mechanisms involved in ALS and SBMA using induced pluripotent stem cells (iPSC).
What are the molecular mechanisms involved in ALS and SBMA? An autosomal dominant form of ALS, named ALS8, is caused by a mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) which causes a change of a Proline to a Serine at position 56 (VAPBP56S). The VAPB protein has also been associated with sporadic ALS and implicated in several ALS pathogenic mechanisms, such as mitochondrial dysfunction, abnormal protein aggregation, and endoplasmic reticulum (ER) stress. By using patient-derived iPSC motor neurons (MNs) we have associated the VAPB mutation with mitochondrial depolarization and decreases in oxygen consumption rate (OCR). We have also identified dysregulation of the mTOR pathway and altered electrophysiological activity in VAPBP56S motor neurons. Notably, SBMA patients differ from ALS patients in disease presentation. In addition to the neuromuscular manifestation, SBMA patients also display signs of androgen insensitivity, due to a trinucleotide CAG repeat expansion in the androgen receptor (AR), which is the mutation responsible for SBMA. This mutation puts SBMA in a group of nine polyglutamine (polyQ) repeat expansion diseases that includes Huntington’s disease (HD). In the case of SBMA, muscle biopsies of SBMA patients reveal evidence for both neurogenic atrophy and myopathy. Recently, it has been demonstrated that termination of human polyQ-AR expression from muscle in an SBMA mouse model rescues all disease phenotypes. To investigate a possible effect of muscles on motor neurons using our human stem cell model, we have established a skeletal muscle differentiation from iPSCs. We have ongoing genomic and biochemistry studies to identify which intracellular pathway and which cell type should be the therapeutic target in humans for this disease.