Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone.

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.

Distinct sets of lysosomal genes define synucleinopathy and tauopathy.

Neurodegenerative diseases are characterized by distinct protein aggregates, such as those of α-synuclein and tau. Lysosomal defect is a key contributor to the accumulation and propagation of aberrant protein aggregates in these diseases. The discoveries of common proteinopathies in multiple forms of lysosomal storage diseases (LSDs) and the identification of some LSD genes as susceptible genes for those proteinopathies suggest causative links between LSDs and the proteinopathies. The present study hypothesized that defects in lysosomal genes will differentially affect the propagation of α-synuclein and tau proteins, thereby determining the progression of a specific proteinopathy. We established an imaging-based high-contents screening (HCS) system in Caenorhabditis elegans (C. elegans) model, by which the propagation of α-synuclein or tau is measured by fluorescence intensity. Using this system, we performed RNA interference (RNAi) screening to induce a wide range of lysosomal malfunction through knock down of 79 LSD genes, and to obtain the candidate genes with significant change in protein propagation. While some LSD genes commonly affected both α-synuclein and tau propagation, our study identified the distinct sets of LSD genes that differentially regulate the propagation of either α-synuclein or tau. The specificity and efficacy of these LSD genes were retained in the disease-related phenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentially regulate the propagation of α-synuclein and tau, and offer a steppingstone to understanding disease specificity. [BMB Reports 2023; 56(12): 657-662].

The Correlation Between Cage Subsidence, Bone Mineral Density, and Clinical Results in Posterior Lumbar Interbody Fusion.

STUDY DESIGN: A retrospective review of prospectively collected radiographic and clinical data. OBJECTIVE: This study aims to investigate the relationship between cage subsidence and bone mineral density (BMD), and to reveal the clinical implications of cage subsidence. SUMMARY OF BACKGROUND DATA: Posterior lumbar interbody fusion (PLIF) has become one of the standard treatment modality for lumbar degenerative disease. However, cage subsidence might result in recurrent foraminal stenosis and deteriorate the clinical results. Furthermore, numbers of osteoporosis patients who underwent PLIF are increasing. Therefore, the information on the correlations between cage subsidence, BMD, and clinical results will be of great significance. MATERIALS AND METHODS: A total 139 segments was included in this retrospective study. We examined functional rating index (Visual Analogue Scale for pain, Oswestry Disability Index, Short Form-36 score) preoperatively, and investigated their changes after postoperative 1 year. Correlation between cage subsidence and clinical scores was investigated. Plain anteroposterior and lateral radiograph were taken preoperatively and postoperatively and during follow-up. Preoperative BMD and subsidence measured by postoperative 1 year 3-dimensional computed tomography were achieved and their correlation was assessed. RESULTS: All postoperative clinical scores improved significantly compared with preoperative ones (pain Visual Analogue Scale: 7.34-2.89, Oswestry Disability Index: 25.34-15.86, Short Form-36: 26.45-16.46, all P<0.001). BMD showed significant weak correlation with subsidence (r=-0.285, P<0.001). Severe osteoporotic segments (T score <-3.0) had more risk to develop severe subsidence (>3 mm) compared with the segments in which T score were higher than -3.0 (P=0.012), and its odds ratio was 8.44. Subsidence had no significant correlation with all clinical scores. CONCLUSIONS: This study revealed that cage subsidence is relevant to BMD. However, it was demonstrated that subsidence is not related to the clinical deterioration. Therefore, PLIF procedure which is conducted carefully can be a good surgical option to treat lumbar degenerative disease for osteoporotic patients.

Retrograde intramedullary nailing for periprosthetic supracondylar fractures of the femur after total knee arthroplasty.

BACKGROUND: Periprosthetic supracondylar fractures of the femur after total knee arthroplasty are not common but are usually difficult to treat due to the advanced age of patients and frequently accompanying osteoporosis. Retrograde intramedullary nailing can be effective in promoting healing of these fractures by providing sufficient stability, but the number of beneficiaries is small due to its limited applicability and the postoperative function has rarely been assessed. This study evaluated the efficacy of retrograde intramedullary nailing for the treatment of periprosthetic supracondylar fractures of the femur using the clinical outcomes. METHODS: Between January 2000 and May 2006, 9 patients (10 knees) with periprosthetic supracondylar fractures of the femur underwent retrograde intramedullary nailing. An open reduction and additional fixation using a shape memory alloy ring were used in 3 of them in whom a closed reduction was not successful. The clinical and radiographic findings were reviewed retrospectively in 7 patients (8 knees), excluding 2 who were unavailable for a follow-up assessment due to death. The mean follow-up period was 39 months (range, 24 to 82 months). The union and alignment of the fracture were assessed radiographically. The postoperative function was evaluated using Sanders' criteria. RESULTS: Radiographic union was obtained in all patients after an average of 13 weeks (range, 12 to 15 weeks) postoperatively. No postoperative infection, heterotopic ossification and component loosening were observed. After union, the coronal alignment averaged 0.1 degrees valgus (range, 3.6 degrees varus to 2.6 degrees valgus) and the mean sagittal alignment was 1.9 degrees of extension (range, 0.9 degrees of flexion to 6.3 degrees of extension). The mean range of motion was 103 degrees (range, 90 degrees to 120 degrees) postoperatively. At the last follow up, there were 1 excellent, 5 good and 2 fair results according to Sanders' criteria. CONCLUSIONS: With retrograde intramedullary nailing, excellent fracture union and good functional recovery were obtained in patients with periprosthetic supracondylar fractures.