Expression of Human Gaucher Disease Gene GBA Generates Neurodevelopmental Defects and ER Stress in Drosophila Eye

Suzuki, Tsuyoshi; Shimoda, Masami; Ito, Kenichiro; Hanai, Shuji; Aizawa, Hitoshi; Kato, Takeshi; Kawasaki, Kazunori; Yamaguchi, Terumi; Ryoo, Hyung Don; Goto‐Inoue, Naoko; Setou, Mitsutoshi; Tsuji, Shoji; Ishida, Norio

doi:10.1371/journal.pone.0069147

Cited by 59 publications

(42 citation statements)

References 34 publications

(43 reference statements)

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“…In addition to NCSCs, α-synuclein accumulation has been reduced by ambroxol in SH-SY5Y overexpressing cell lines and transgenic SNCA/SNCA mice (McNeill et al, 2014;. In Drosophila fly models ambroxol reversed GBA mutant effects, including ER stress, reduced GCase activity and motor defects (Maor et al, 2016;Sanchez-Martinez et al, 2016;Suzuki et al, 2013). Transgenic mice carrying the L444P/+ gene and wild-type mice also had increased GCase activity in response to ambroxol (Luan et al, 2013;, the same was observed recently in healthy nonhuman primates (Migdalska-Richards et al, 2017).…”

Section: Administration Of Small Molecular Chaperones Have Been Reporsupporting

confidence: 68%

Insights into the structural biology of Gaucher disease

Smith

Mullin

Schapira

2017

Experimental Neurology

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Gaucher disease, the most common lysosomal storage disorder, is caused by mutations in the gene encoding the acid-β-glucosidase lysosomal hydrolase enzyme that cleaves glucocerebroside into glucose and ceramide. Reduced enzyme activity and impaired structural stability arise due to >300 known disease-causing mutations. Several of these mutations have also been associated with an increased risk of Parkinson disease (PD). Since the discovery of the acid-β-glucosidase X-ray structure, there have been major advances in our understanding of the structural properties of the protein. Analysis of specific residues has provided insight into their functional and structural importance and provided insight into the pathogenesis of Gaucher disease and the contribution to PD. Disease-causing mutations are positioned throughout the acid-β-glucosidase structure, with many located far from the active site and thus retaining some enzymatic activity however, thus far no clear relationship between mutation location and disease severity has been established. Here, we review the crystal structure of acid-β-glucosidase, while highlighting important structural aspects of the protein in detail. This review discusses the structural stability of acid-β-glucosidase, which can be altered by pH and glycosylation, and explores the relationship between known Gaucher disease and PD mutations, structural stability and disease severity.

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Section: Administration Of Small Molecular Chaperones Have Been Reporsupporting

confidence: 68%

Insights into the structural biology of Gaucher disease

Smith

Mullin

Schapira

2017

Experimental Neurology

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“…Increased release of calcium from the ER has also been observed in iPS‐derived neurons or fibroblasts from patients with GBA mutations and PD. Drosophila models expressing PD‐associated GBA mutations have also exhibited activation of the UPR . Drosophila does not have a homologue of α‐synuclein, and therefore the loss of dopaminergic neurons and locomotor defects were independent of α‐synuclein pathology.…”

Section: Er Stress Mitochondrial Dysfunction and Neuroinflammationmentioning

confidence: 99%

“…In Drosophila , both ambroxol and isofagomine have been shown to effectively reduce the ER stress induced by mutant human GBA and also reverse the locomotor deficit observed in these models .…”

Section: Therapy For Gcase Deficiency In Pdmentioning

confidence: 99%

The role of glucocerebrosidase in Parkinson disease pathogenesis

2018

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GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of α-synuclein. A hallmark of PD is the presence of intraneuronal protein inclusions called Lewy bodies, which are composed mainly of α-synuclein. Cellular and animal models of GCase deficiency result in lysosomal dysfunction, and in particular the autophagy lysosome pathway, resulting in the accumulation of α-synuclein. Some forms of mutant GCase unfold in the endoplasmic reticulum activating the unfolded protein response, which might also contribute to PD pathogenesis. It has also been suggested that accumulation of GCase substrates glucosylceramide/glucosylsphingosine may contribute to GBA-PD pathogenesis. Mitochondrial dysfunction and neuroinflammation are associated with GCase deficiency and have also been implicated in the aetiology of PD. This review discusses these points and highlights potential treatments that might be effective in treating GCase deficiency in PD.

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“…Takahiro Suzuki (currently, Shigray Inc.), who was a graduate student ( the University of Tsukuba) in Ishida Group of Clock Gene, AIST, succeeded in creating a model animal by transforming a variant human Gaucher disease gene in a Drosophila compound eye. [37] Gaucher disease is a lysosome disease Term 14 that is specified as one of diseases in the Research on Measures for Intractable Diseases Project of the Ministry of Health, Labour and Welfare. Due to a genetic mutation, the activity of enzymes called glucocerebrosidase is lost before birth.…”

Section: Essence Of Dementia Learned From Drosophila Geneticsmentioning

confidence: 99%

Toward overcoming neurodegenerative disease by the circadian molecular clock study

Ishida

2017

Synthesiology English edition

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Drosophila clock gene, Period, was detected in birds, mice, and humans. This paper got me excited. That is because the research of genes involved in behavior was the reason I jumped into this field. Furthermore, it was my dream to study behavior from genes ever since I became interested in psychology and behavior science in high school. At that time, for circadian clock genes, the Period gene of Drosophila was cloned for the first time in 1984, but it was a total mystery why such a gene could affect complex behavior. Therefore, I immediately shifted the target to clone circadian clock genes in mammals, and embarked on the labor of isolating and sequencing candidate clones every day. However, the sequences I obtained were all an RNA repetitive sequence (ACNGGC) of a specific RNA region partially similar to the Period gene, and I was unable to obtain the targeted Period homologous gene composed of 1,100 or more amino acids from mice. Looking back, this seemed to be the noncoding RNA that is the current megatrend in molecular biology. Excellent colleagues who joined the Biological Clock Group during this time included the following people: Miwa Matsui (in situ hybridization); Masae Kurama (diurnal expression of endothelin); Kaname Saida (cloning of endothelin family); Koichiro Kako [establishment of EMSA method and a role

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Expression of Human Gaucher Disease Gene GBA Generates Neurodevelopmental Defects and ER Stress in Drosophila Eye

Cited by 59 publications

References 34 publications

Insights into the structural biology of Gaucher disease

Insights into the structural biology of Gaucher disease

The role of glucocerebrosidase in Parkinson disease pathogenesis

Toward overcoming neurodegenerative disease by the circadian molecular clock study

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