The GBA1 D409V mutation exacerbates synuclein pathology to differing extents in two alpha-synuclein models

Area of Science:

• Neuroscience
• Genetics
• Biochemistry

Background:

• Heterozygous mutations in the GBA1 gene, encoding glucocerebrosidase (GCase), are the most common genetic risk factor for Parkinson's disease (PD).
• Reduced GCase activity is experimentally linked to alpha-synuclein (aSyn) accumulation, a key protein implicated in PD pathology.

Purpose of the Study:

• To investigate the relationship between alpha-synuclein (aSyn) and GCase activity in Parkinson's disease (PD) pathogenesis.
• To develop and characterize novel mouse models that explore aSyn pathology within the context of reduced GCase activity.

Main Methods:

• Development of two mouse models: 1) Constitutive overexpression of human aSyn in GBA1 D409V homozygous mice. 2) Stereotactic injection of alpha-synuclein pre-formed fibrils (PFFs) into the striatum of GBA1 D409V knock-in mice.
• Assessment of aSyn pathology, nigrostriatal system integrity, and motor function (grip strength) in the developed mouse models.

Main Results:

• The first model (aSyn overexpression in GBA1 D409V mice) exhibited increased aSyn pathology and grip strength deficits but a largely intact nigrostriatal system.
• The second model (aSyn PFF injection in GBA1 D409V mice) did not show exacerbated pathology, indicating the GBA1 D409V mutation did not worsen PFF-induced pathology.

Conclusions:

• The study highlights the complex interplay between alpha-synuclein and GCase activity in Parkinson's disease.
• The findings underscore the critical impact of experimental model design on the ability to accurately recapitulate the relationship between these proteins in PD-related pathology.