Trends in Neurosciences
ReviewCan GBA1-Associated Parkinson Disease Be Modeled in the Mouse?
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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