Trends in Neurosciences
Volume 42, Issue 9, September 2019, Pages 631-643
Journal home page for Trends in Neurosciences

Review
Can GBA1-Associated Parkinson Disease Be Modeled in the Mouse?

https://doi.org/10.1016/j.tins.2019.05.010Get rights and content

Highlights

  • Mutations in GBA1, the gene encoding the lysosomal lipid-degrading enzyme GCase, increase the risk for developing Parkinson disease (PD).

  • The mechanisms by which GBA1 mutations induce susceptibility to PD are still not clear, in part because of the challenges in generating appropriate disease models.

  • GCase is reduced in PD brains in the absence of GBA1 mutations, highlighting the inverse relationship between GCase and α-synuclein, and the potential of GCase augmentation as a therapeutic strategy for sporadic PD.

  • Different GBA1-associated PD mouse models provide important insights into the mechanisms underlying the contribution of GBA1 to PD risk, and offer opportunities for testing different therapeutic approaches.

  • Here, we provide a comprehensive summary of the design and phenotype of the many current GBA1-associated PD models, and highlight each model’s strengths and limitations.

  • Evaluation of the different strategies used to model GBA1-associated PD underscores some of the inherent challenges associated with modeling a genetic disease risk factor, which are more broadly relevant to the design of risk models for other disorders as well.

Homozygous and heterozygous mutations in GBA1, the gene implicated in Gaucher disease, increase the risk and severity of Parkinson disease (PD). We evaluated the design, phenotype, strengths, and limitations of current GBA1-associated PD mouse models. Although faithful modeling of a genetic risk factor poses many challenges, the different approaches taken were successful in revealing predisposing abnormalities in heterozygotes for GBA1 mutations and demonstrating the deleterious effects of GBA1 impairment on the PD course in PD models. GBA1-PD models differ in key parameters, with no single model recapitulating all aspects of the GBA1-PD puzzle, emphasizing the importance of selecting the proper in vivo model depending on the specific molecular mechanism or potential therapy being studied.

Section snippets

The GBA1-PD Puzzle

Parkinson disease (PD; see Glossary) is a common movement disorder characterized by progressive dopaminergic neurodegeneration and the formation of Lewy bodies, mainly composed of insoluble aggregates of α-synuclein [1]. Although genomic duplications or triplications and missense mutations in the α-synuclein encoding gene SNCA, as well as mutations in other genes like LRRK2, VPS35, and PARK2 lead to rare familial forms of PD, PD is generally considered a multifactorial disorder. It is likely

GBA1-Associated PD Mouse Models

Faithful modeling of GBA1-associated PD is challenged by many factors (Box 1). Nevertheless, a variety of GBA1-associated PD murine models have been designed and characterized, providing important insights regarding the mechanisms underlying the contribution of GBA1 to PD risk and the opportunity to test different therapeutic approaches. Nonmurine models such as the fly and fish have also been used to study the GBA1-PD connection 35., 36.. The first attempts to model GBA1-associated PD in the

Genetic Models

Since patients with GD carrying two GBA1 mutations and GD carriers with a single GBA1 mutation are both at risk for developing PD, researchers have emulated these two conditions through a variety of genetic mouse models featuring homozygous genotypes, single point mutations, or GBA1 haploinsufficiency.

Chemical Model: Conduritol-β-Epoxide (CBE)

GCase activity in vivo can be pharmacologically inhibited by administration of the GCase inhibitor CBE via intraperitoneal injections 37., 75.. The extent of GCase inhibition, amount of substrate accumulation, neuropathological changes, and symptom severity resulting from CBE treatment heavily depend on the CBE treatment regimen, including mouse age and strain 76., 77.. Various CBE treatment regimens were employed to study the role of GCase in PD pathogenesis, starting from higher doses that

Concluding Remarks

An evaluation of the different strategies used to model GBA1-associated PD has direct implications for the design of models for other disorders. Modeling a disease risk factor is particularly challenging, as described in Box 1, and there remain gaps in our understanding of how to best model GBA1-associated PD (see Outstanding Questions). Nevertheless, attempts to model GBA1-associated PD in mice revealed several fundamental insights. First, pronounced α-synuclein pathology may develop in

Acknowledgments

This work was supported by the Intramural Research Program of the National Human Genome Research Institute and the National Institutes of Health (USA) as well as the NINDS Competitive Postdoctoral Fellowship Award (T.F-B).

Glossary

A53T-SNCA and A30P-SNCA mice
transgenic PD mouse models generated by overexpression of mutant forms of human α-synuclein associated with familial PD. Several models have been described, differing in α-synuclein expression pattern and levels, and in the degree of the resulting neuropathological and behavioral changes.
CBE
conduritol-β-epoxide; an irreversible GCase inhibitor. Repeated intraperitoneal CBE injections in mice result in a GD-like phenotype.
Chemical GCase chaperones
small molecules that

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