Corrigendum: Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation

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Loss of glucocerebrosidase 1 activity causes lysosomal dysfunction and alpha-synuclein aggregation

Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes beta-glucocerebrosidase 1 (GCase 1), a lysosomal hydrolase. Homozygous mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disease, while heterozygous mutations are strong risk factors for Parkinson's disease. However, whether loss of GCase 1 activity is sufficient for lysosomal dysfunction has not been clearly determined. Here, we generated human neuroblastoma cell lines with nonsense mutations in the GBA1 gene using zinc-finger nucleases. Depending on the site of mutation, GCase 1 activity was lost or maintained. The cell line with GCase 1 deficiency showed indications of lysosomal dysfunction, such as accumulation of lysosomal substrates, reduced dextran degradation and accumulation of enlarged vacuolar structures. In contrast, the cell line with C-terminal truncation of GCase 1 but with intact GCase 1 activity showed normal lysosomal function. When alpha-synuclein was overexpressed, accumulation and secretion of insoluble aggregates increased in cells with GCase 1 deficiency but did not change in mutant cells with normal GCase 1 activity. These results demonstrate that loss of GCase 1 activity is sufficient to cause lysosomal dysfunction and accumulation of alpha-synuclein aggregates.

ATP13A2/PARK9 Deficiency Neither Cause Lysosomal Impairment Nor Alter alpha-Synuclein Metabolism in SH-SY5Y Cells

Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis. Here, we set out to investigate the role of ATP13A2 in lysosomal function and in metabolism of alpha-synuclein, another PD-linked protein whose accumulation is implicated in the pathogenesis. We generated non-sense mutations in both copies of ATP13A2 gene in SH-SY5Y human neuroblastoma cells. We examined lysosomal function of ATP13A2-/- cells by measuring the accumulation of lysosomal substrate proteins, such as p62 and polyubiquitinated proteins, induction of acidic compartments, and degradation of ectopically introduced dextran. None of these measures were altered by ATP13A2 deficiency. The steady-state levels of alpha-synuclein in cells or secretion of this protein were unaltered either in ATP13A2-/- compared to the normal cells. Therefore, the proposed roles of ATP13A2 in lysosomal functions may not be generalized and may depend on the cellular context. The ATP13A2-/- cells generated in the current study may provide a useful control for studies on the roles of PD genes in lysosomal functions.

Long-Term Tolerability of Escitalopram in Korean Adolescents

OBJECTIVES: We investigated the long-term tolerability of escitalopram in Korean adolescents. METHODS: The subjects were 37 adolescents, who had been diagnosed with depressive disorder in accordance to DSM-IV. Clinical effectiveness was assessed by Clinical Global Impression-Improvement (CGI-I) scale at the final follow-up visit. Tolerability was assessed through a medical record of the reason for discontinuation of escitalopram and documented adverse events. RESULTS: The mean duration of treatment was 78.1+/-89.5 days, and the mean dosage was 10.0+/-4.4mg/day. Out of the total 37 patients, two (5%) patients sustained use of escitalopram. Twelve patients (32.4%) discontinued use of escitalopram due to target symptom remission, and 23 patients (61.9%) due to insufficient efficacy. Six patients (16.2%) had at least one documented adverse event. However, no suicidal ideation or self-injurious behavior was reported. Significant differences in clinical symptom improvement efficacy were seen between the patients who were receiving escitalopram for less than 8 weeks (4.3%, 1/13) and those for more than 8 weeks (92.9%, 13/14). There was no significant difference between the tolerability of monotherapy compared to the concomitant use group. CONCLUSION: The results of this study suggest that long-term use of escitalopram may result in superior efficacy than short-term use, and is tolerable in Korean adolescents with depression.