Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Nahid Tayebi; Loukia Parisiadou; Bahafta Berhe; Ashley N. Gonzalez; Jenny Serra-Vinardell; Raphael J. Tamargo; Emerson Maniwang; Zachary Sorrentino; Hideji Fujiwara; Richard J. Grey; Shahzeb Hassan; Yotam N. Blech-Hermoni; Chuyu Chen; Ryan McGlinchey; Chrissy Makariou-Pikis; Mieu Brooks; Edward I. Ginns; Daniel S. Ory; Benoit I. Giasson; Ellen Sidransky

doi:10.1016/j.ymgme.2017.11.001

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Nahid Tayebi, Loukia Parisiadou, Bahafta Berhe, Ashley N. Gonzalez, Jenny Serra-Vinardell, Raphael J. Tamargo, Emerson Maniwang, Zachary Sorrentino, Hideji Fujiwara, Richard J. Grey, Shahzeb Hassan, Yotam N. Blech-Hermoni, Chuyu Chen, Ryan McGlinchey, Chrissy Makariou-Pikis, Mieu Brooks, Edward I. Ginns, Daniel S. Ory, Benoit I. Giasson, Ellen Sidransky^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCA^A53T) transgene were crossed with heterozygous null gba mice (gba^+/−). Survival analysis of 84 mice showed that in gba^+/−//SNCA^A53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba^+/+//SNCA^A53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCA^A53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCA^A53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.

Original language	English (US)
Pages (from-to)	198-208
Number of pages	11
Journal	Molecular Genetics and Metabolism
Volume	122
Issue number	4
DOIs	https://doi.org/10.1016/j.ymgme.2017.11.001
State	Published - Dec 2017

Funding

This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health, and a grant from the National Institute of Neurological Disorders and Stroke (NS089622). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility (P30 DK020579) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health , and a grant from the National Institute of Neurological Disorders and Stroke ( NS089622 ). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility ( P30 DK020579 ) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985 .

Keywords

Aggregates
Gaucher disease
Glucocerebrosidase
Mouse model
Parkinson disease
α-synuclein

ASJC Scopus subject areas

Genetics
Endocrinology
Molecular Biology
Biochemistry
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ymgme.2017.11.001

Cite this

Tayebi, N., Parisiadou, L., Berhe, B., Gonzalez, A. N., Serra-Vinardell, J., Tamargo, R. J., Maniwang, E., Sorrentino, Z., Fujiwara, H., Grey, R. J., Hassan, S., Blech-Hermoni, Y. N., Chen, C., McGlinchey, R., Makariou-Pikis, C., Brooks, M., Ginns, E. I., Ory, D. S., Giasson, B. I., & Sidransky, E. (2017). Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course. Molecular Genetics and Metabolism, 122(4), 198-208. https://doi.org/10.1016/j.ymgme.2017.11.001

@article{3d4cb9dbb7374db7ac3a92b4c839e73e,

title = "Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course",

abstract = "Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.",

keywords = "Aggregates, Gaucher disease, Glucocerebrosidase, Mouse model, Parkinson disease, α-synuclein",

author = "Nahid Tayebi and Loukia Parisiadou and Bahafta Berhe and Gonzalez, {Ashley N.} and Jenny Serra-Vinardell and Tamargo, {Raphael J.} and Emerson Maniwang and Zachary Sorrentino and Hideji Fujiwara and Grey, {Richard J.} and Shahzeb Hassan and Blech-Hermoni, {Yotam N.} and Chuyu Chen and Ryan McGlinchey and Chrissy Makariou-Pikis and Mieu Brooks and Ginns, {Edward I.} and Ory, {Daniel S.} and Giasson, {Benoit I.} and Ellen Sidransky",

note = "Funding Information: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health, and a grant from the National Institute of Neurological Disorders and Stroke (NS089622). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility (P30 DK020579) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985. Funding Information: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health , and a grant from the National Institute of Neurological Disorders and Stroke ( NS089622 ). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility ( P30 DK020579 ) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985 . Publisher Copyright: {\textcopyright} 2017",

year = "2017",

month = dec,

doi = "10.1016/j.ymgme.2017.11.001",

language = "English (US)",

volume = "122",

pages = "198--208",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

publisher = "Academic Press Inc.",

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Tayebi, N, Parisiadou, L, Berhe, B, Gonzalez, AN, Serra-Vinardell, J, Tamargo, RJ, Maniwang, E, Sorrentino, Z, Fujiwara, H, Grey, RJ, Hassan, S, Blech-Hermoni, YN, Chen, C, McGlinchey, R, Makariou-Pikis, C, Brooks, M, Ginns, EI, Ory, DS, Giasson, BI & Sidransky, E 2017, 'Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course', Molecular Genetics and Metabolism, vol. 122, no. 4, pp. 198-208. https://doi.org/10.1016/j.ymgme.2017.11.001

TY - JOUR

T1 - Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

AU - Tayebi, Nahid

AU - Parisiadou, Loukia

AU - Berhe, Bahafta

AU - Gonzalez, Ashley N.

AU - Serra-Vinardell, Jenny

AU - Tamargo, Raphael J.

AU - Maniwang, Emerson

AU - Sorrentino, Zachary

AU - Fujiwara, Hideji

AU - Grey, Richard J.

AU - Hassan, Shahzeb

AU - Blech-Hermoni, Yotam N.

AU - Chen, Chuyu

AU - McGlinchey, Ryan

AU - Makariou-Pikis, Chrissy

AU - Brooks, Mieu

AU - Ginns, Edward I.

AU - Ory, Daniel S.

AU - Giasson, Benoit I.

AU - Sidransky, Ellen

N1 - Funding Information: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health, and a grant from the National Institute of Neurological Disorders and Stroke (NS089622). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility (P30 DK020579) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985. Funding Information: This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and the National Institutes of Health , and a grant from the National Institute of Neurological Disorders and Stroke ( NS089622 ). The authors also thank the NHGRI Embryonic Stem Cell and Transgenic Mouse Core Facility, the NHGRI Animal Program and the Washington University Metabolomics Facility ( P30 DK020579 ) for their support, and Ms. Julia Fekecs for her help in preparing the figures. Loukia Parisiadou was supported by NIH grant: 1 R01 NS097901 and Daniel Ory by NINDS grant NS081985 . Publisher Copyright: © 2017

PY - 2017/12

Y1 - 2017/12

N2 - Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.

AB - Mutations in GBA1 encountered in Gaucher disease are a leading risk factor for Parkinson disease and associated Lewy body disorders. Many GBA1 mutation carriers, especially those with severe or null GBA1 alleles, have earlier and more progressive parkinsonism. To model the effect of partial glucocerebrosidase deficiency on neurological progression in vivo, mice with a human A53T α-synuclein (SNCAA53T) transgene were crossed with heterozygous null gba mice (gba+/−). Survival analysis of 84 mice showed that in gba+/−//SNCAA53T hemizygotes and homozygotes, the symptom onset was significantly earlier than in gba+/+//SNCAA53T mice (p-values 0.023–0.0030), with exacerbated disease progression (p-value < 0.0001). Over-expression of SNCAA53T had no effect on glucocerebrosidase levels or activity. Immunoblotting demonstrated that gba haploinsufficiency did not lead to increased levels of either monomeric SNCA or insoluble high molecular weight SNCA in this model. Immunohistochemical analyses demonstrated that the abundance and distribution of SNCA pathology was also unaltered by gba haploinsufficiency. Thus, while the underlying mechanism is not clear, this model shows that gba deficiency impacts the age of onset and disease duration in aged SNCAA53T mice, providing a valuable resource to identify modifiers, pathways and possible moonlighting roles of glucocerebrosidase in Parkinson pathogenesis.

KW - Aggregates

KW - Gaucher disease

KW - Glucocerebrosidase

KW - Mouse model

KW - Parkinson disease

KW - α-synuclein

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JO - Molecular Genetics and Metabolism

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IS - 4

ER -

Glucocerebrosidase haploinsufficiency in A53T α-synuclein mice impacts disease onset and course

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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