The hereditary motor neuronopathies (HMN) are a heterogeneous group of disorders involving the selective death of motor neurons without complete understanding of causes. We propose to study the disease mechanism of HMN by investigating the role of a novel ER membrane protein in motor neuron survival. We have found that lose of this novel protein in a mouse model resulted selective motor neuron degeneration, consistent with a childhood-onset phenotype of HMN. Importantly, we have identified an HMN family with a childhood-onset patient who inherited double mutations of the gene coded for this protein from unaffected parents. We further found that cells from the human HMN patient were particularly vulnerable to ER stress. Therefore, we hypothesize that the death of motor neurons in an early onset HMN is caused by increased ER stress. To test this hypothesis, we will generate induced pluripotent stem cells (iPSCs) from the HMN patient and test if these cells have difficult to differentiate into normal motor neurons. We will further investigate if cells from patient show elevated ER stress contributing to the vulnerability of motor neurons. We will also test if blockade of ER stress by drugs can rescue iPSC-derived motor neurons. These studies will not only elucidate the disease mechanisms of the childhood-related HMN but also identify potential drug targets for its intervention. The information is also useful to treating other neurological disorders caused by ER stress.
Thousands of Californians are suffering from motor dysfunctions due to various degree of motor neuron degeneration, especially from childhood-onset motor neuron diseases. There is no cure for these diseases and current treatments to relieve symptoms are costly and ineffective. Understanding the disease mechanism and identifying novel drug targets are critical for developing effective treatment for these diseases. Recent technical advancements in human induced pluripotent stem cell (iPSC) production have revolutionized their potential applications in studying disease mechanisms and drug targets in most relevant model system and have provided enormous hope for these patients. Based on our studies of the critical role of a novel protein in a mouse model of hereditary motor neuronopathies (HMN), we propose to elucidate the disease mechanism and test the effect of drugs directly in human iPSCs from a patient of childhood-onset HMN. These studies will not only elucidate the disease mechanism of the childhood-related HMN and identify potential drug targets for its intervention but also are useful for treating other neurological disorders caused by similar pathogenic processes. Therefore, the long-term benefit of the proposed work is to benefit California’s financial status in reducing the cost of treating these patients. It will also promote California’s leadership in the field of stem cell research in general and childhood-onset neurological disorders research in particular.