ALPHA-SYNUCLEIN EFFECTS IN GBA PARKINSON’S MODEL: EARLY STRIATAL CIRCUIT REMODELING

Mutations in the GBA gene are the most common genetic risk factor for Parkinson’s disease (PD) and are associated with reduced glucocerebrosidase (GCase) activity and enhanced vulnerability to alpha-synuclein (Syn) pathology. Syn is a lipid-binding protein physiologically enriched at presynaptic terminals, where it regulates vesicle trafficking and membrane organization through interactions with phospholipids. Whether this role translates into circuit dysfunction when Syn aggregates in the context of pre-existing lysosomal impairment remains unclear.
We combined behavioral, electrophysiological, biochemical, and lipidomic approaches to investigate basal ganglia circuit function in wild-type (WT) and GBA heterozygous (Het; GBA1 L444P/+) mice at an early stage of pathology following bilateral striatal injection of Syn preformed fibrils (Syn-PFFs).
At baseline, Het mice showed a reduction of GCase activity across multiple brain regions. Striatal spiny projection neurons exhibited preserved intrinsic excitability but reduced spontaneous excitatory transmission and altered paired-pulse ratio, while long-term potentiation (LTP) remained intact. Behaviorally, Het mice displayed mild motor impairment without cognitive deficits.
Following Syn-PFF injection, WT mice developed increased neuronal excitability and loss of striatal LTP. In contrast, in Het mice, Syn pathology further reduced GCase activity selectively in the midbrain but restored spontaneous synaptic activity, preserved LTP, and rescued motor performance. Preliminary lipidomic analyses reveal genotype-dependent alterations that were similarly normalized in Het mice after Syn injection. In Het neurons, Syn functionally remodels lipid-altered membranes, transiently restoring synaptic performance while its detrimental effects remain restricted to lysosomal vulnerability in selective regions.
These findings reveal a non-linear interaction between GBA deficiency and Syn pathology.