The dbl-PAC-Tg(SNCAA53T);Snca-/-; GbaL444P/+ mice harbor a Snca knockout allele, two independently inserted transgenes encoding the human A53T-mutant alpha-synuclein associated with autosomal dominant Parkinson's disease and the L444P mutation in the Gba (glucosidase, beta, acid) gene associated with the alpha-synucleinopathy, Gaucher disease. 

In mice homozygous for the two transgenes and the Snca KO, expression of endogenous mouse alpha-synuclein is abolished and replaced by alpha-synuclein*A53T from the four total insertions of the PAC- Tg(SNCAA53T) resulting in a Parkinson’s phenotype (see Jackson Laboratory Stock No. <a href="https://www.jax.org/strain/010799">010799</a>). The addition of the heterozygous Gaucher mutation, L444P, reduces glucocerebrosidase (GBA) activity by 40%, reduces SNCA degradation, and results in the accumulation SNCA protein in culture. The enzyme GBA is involved in lysosomal protein degradation and thus in the lysosomal-autophagy pathway mainly responsible for SNCA degradation. 
Heterozygous carriers of Gaucher disease have an increased risk for Parkinson’s disease.

14 to 15 month old mice exhibit an enteric nervous system dysfunction characterized by constipation and reduced whole gut transit time (males only). Motor activity is impaired as well as exploratory behavior, and endurance and coordination on the rotarod. Accumulation of human pSer129 SNCA is observed earlier (15 months) than in the A53T mice, although there is no increase in absolute SNCA levels.

Combining these two mouse models of Parkinson’s and Gaucher disease results in an exacerbation of the motor and gastrointestinal deficits found in the Parkinson’s A53T model alone.

The dbl-PAC-Tg(SNCAA53T);Snca-/-; GbaL444P/+ mice harbor a Snca knockout allele, two transgenes encoding the human A53T-mutant alpha-synuclein associated with autosomal dominant Parkinson's disease and the L444P mutation in the Gba (glucosidase, beta, acid) gene associated with the alpha-synucleinopathy, Gaucher disease. Combining these two mouse models of Parkinson&rsquo;s and Gaucher disease results in an exacerbation of the motor and gastrointestinal deficits found in the Parkinson&rsquo;s A53T model alone.

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