Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

Yang, Na; Lee, Yu Na; Lee, He Jin; Kim, Yoon Suk; Lee, Seung-Jae

doi:10.1515/hsz-2012-0322

Cited by 15 publications

(10 citation statements)

References 88 publications

(107 reference statements)

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“…Several potential mechanisms leading to α-synuclein aggregation have been proposed. 12 Elucidation of the mechanism underlying the pathogenic actions of GBA1 mutations will help us identify rational therapeutic strategies for LBDs and GD.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic studies have shown that heterozygous carriers of mutations in GBA1 are at higher risk for PD than the general population. 12 For example, patients with PD are approximately five times more likely to carry GBA1 mutations than healthy control subjects. 13 Compared with control group, the incidence of parkinsonism is increased 6- to 17-folds in patient group with type1 GD.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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Lysosomal dysfunction is a common pathological feature of neurodegenerative diseases. GTP-binding protein type A1 (GBA1) encodes β-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 α-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 α-synuclein aggregates.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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“… 38 Heterozygous carriers of GBA1 mutations are at a higher risk for PD. 39 , 40 It has been shown that about 75% of Lewy bodies, a pathological hallmark of PD, colocalized with GCase 1 in brains of PD and DLB patients with heterozygous GBA1 mutations. 41 These results suggest that lysosomal enzyme deficiency is associated with the development of PD.…”

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confidence: 99%

Haploinsufficiency of cathepsin D leads to lysosomal dysfunction and promotes cell-to-cell transmission of α-synuclein aggregates

et al. 2015

Cell Death Dis

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Lysosomal dysfunction has been implicated both pathologically and genetically in neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease (PD). Lysosomal gene deficiencies cause lysosomal storage disorders, many of which involve neurodegeneration. Heterozygous mutations of some of these genes, such as GBA1, are associated with PD. CTSD is the gene encoding Cathepsin D (CTSD), a lysosomal protein hydrolase, and homozygous CTSD deficiency results in neuronal ceroid-lipofuscinosis, which is characterized by the early onset, progressive neurodegeneration. CTSD deficiency was also associated with deposition of α-synuclein aggregates, the hallmark of PD. However, whether partial deficiency of CTSD has a role in the late onset progressive neurodegenerative disorders, including PD, remains unknown. Here, we generated cell lines harboring heterozygous nonsense mutations in CTSD with genomic editing using the zinc finger nucleases. Heterozygous mutation in CTSD resulted in partial loss of CTSD activity, leading to reduced lysosomal activity. The CTSD mutation also resulted in increased accumulation of intracellular α-synuclein aggregates and the secretion of the aggregates. When α-synuclein was introduced in the media, internalized α-synuclein aggregates accumulated at higher levels in CTSD+/− cells than in the wild-type cells. Consistent with these results, transcellular transmission of α-synuclein aggregates was increased in CTSD+/− cells. The increased transmission of α-synuclein aggregates sustained during the successive passages of CTSD+/− cells. These results suggest that partial loss of CTSD activity is sufficient to cause a reduction in lysosomal function, which in turn leads to α-synuclein aggregation and propagation of the aggregates.

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“…Several genes linked to PD have been suggested to function in the lysosomal degradation pathway and in formation of α-synuclein pathology [ 42 , 43 , 44 ]. Here, we generated a human neuroblastoma cell line lacking ATP13A2 and investigated the role of this protein in the general lysosomal function and in α-synuclein metabolism.…”

Section: Introductionmentioning

confidence: 99%

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

Bae

Lee

et al. 2014

Exp Neurobiol

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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 α-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 α-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.

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Glucocerebrosidase, a new player changing the old rules in Lewy body diseases

Cited by 15 publications

References 88 publications

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

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

Haploinsufficiency of cathepsin D leads to lysosomal dysfunction and promotes cell-to-cell transmission of α-synuclein aggregates

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

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