Studies of Hereditary Neurological Disease: Disease Mechanisms

近年来，我们的研究主要集中在三种遗传性运动神经元疾病：由senataxin （SETX）突变引起的肌萎缩侧索硬化症4型（ALS4），由雄激素受体（AR）突变引起的脊髓和球性肌萎缩症（SBMA），以及由SMN蛋白缺乏引起的常染色体隐性脊髓性肌萎缩症（SMA）。具体研究成果包括：

Recently our research has focused on three hereditary motor neuron diseases: amyotrophic lateral sclerosis type 4 (ALS4) due to mutation in senataxin (SETX), spinal and bulbar muscular atrophy (SBMA) due to mutation in the androgen receptor (AR), and autosomal recessive spinal muscular atrophy (SMA) due to deficiency of the protein SMN. Specific research accomplishments include the following: (1) We characterized clinical and molecular features in patients with ALS4 caused by known mutation in SETX, and we developed tools for evaluating other SETX variants. Our study involved 32 patients, including 31 with mutation in SETX at c.1166 T>C (p.Leu389Ser) and 1 with mutation at c.1153 G>A (p.Glu385Lys). Clinical characterization of the patients included neurological examination, blood tests, magnetic resonance imaging (MRI), and dual-energy x-ray absorptiometry (DEXA). Fibroblasts and motor neurons were obtained to model the disease and characterize the molecular alteration in senataxin function. We reported key clinical features of ALS4. Laboratory analysis showed alteration of serum creatine kinase and creatinine in the Leu389Ser ALS4 cohort. MRI showed increased muscle fat fraction in the lower extremities, which correlated with disease duration. DEXA measurements showed that lower extremities are more affected than upper extremities. A cellular assay for SETX function confirmed that like the Leu389Ser mutation, the Glu385Lys variant leads to a decrease in R loops, likely from a gain of function. We identified clinical laboratory and radiological features of ALS4, and hence they should be monitored for disease progression. The molecular characterization of R-loop levels in patient-derived cells provides insight into the disease pathology and assays to evaluate the pathogenicity of candidate mutations in the SETX gene. (2) SBMA is caused by polyglutamine expansion in the AR protein. Using gene expression analysis and ChIP sequencing, we mapped transcriptional changes in genetically engineered patient stem cell-derived motor neurons. We found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. We detected reduced histone acetylation, along with decreased expression of genes encoding compensatory metabolic proteins and reduced substrate availability for mitochondrial function. In addition, we found that pyruvate supplementation corrected this deficiency and improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that results in neurodegeneration.