A pathogenic alpha synuclein variant exacerbates disease progression in a neuron-specific Gba-KO mouse

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• GBA variants are key genetic risk factors for synucleinopathies, including Parkinson's disease and dementia with Lewy bodies.
• The GBA gene encodes glucocerebrosidase, essential for breaking down glycosphingolipids, and has a reciprocal relationship with alpha-synuclein (α-syn).
• Reduced GBA levels are known to increase α-syn levels, but the in vivo neuronal connection requires further investigation.

Purpose of the Study:

• To investigate the in vivo relationship between GBA deficiency and pathogenic α-synuclein (A53T variant) specifically within neurons.
• To determine how combined GBA deficiency and pathogenic α-synuclein affect disease progression and molecular pathology.

Main Methods:

• Generation of a double variant mouse model: neuron-specific Gba-knockout (Gba-KO) mice crossed with mice expressing human pathogenic α-synuclein (A53T).
• Assessment of disease phenotype, including lifespan, weight loss, and brain pathology.
• Biochemical analysis of brain tissue to quantify levels of glucosylceramide, glucosylsphingosine, and phosphorylated α-syn.

Main Results:

• The double variant mouse model exhibited a significantly reduced lifespan and accelerated weight loss compared to neuron-specific Gba-KO mice, indicating a faster disease course.
• Brains of the double variant mice showed elevated glucosylceramide and phosphorylated α-syn levels, but unchanged glucosylsphingosine levels.
• The detrimental effect of pathogenic α-synuclein on lifespan was more pronounced when combined with Gba-KO than with deficiencies in Hexa or Hexb.

Conclusions:

• Pathogenic α-synuclein exacerbates GBA-related disease mechanisms within neurons.
• This interaction leads to an earlier and more severe disease phenotype in synucleinopathies.
• The developed mouse model provides a valuable tool for studying GBA-related synucleinopathies and potential therapeutic strategies.