Gba1, which encodes the lysosomal enzyme glucocerebrosidase (GCase), is involved in sphingolipid metabolism [2]. GCase deficiency leads to abnormal accumulation of its substrates, and this gene is significantly associated with health conditions. Biallelic variants in Gba1 cause Gaucher disease, a lysosomal storage disorder, and carriers of Gba1 variants have an increased risk of developing Parkinson's disease (PD) [2].

In PD, Gba1-associated PD is recognized as a distinct entity within parkinsonian disorders [1]. Gba1 mutations contribute to PD development through mechanisms like 'haploinsufficiency' and 'gain of function' [1]. The 'gain of function' mechanism seems more plausible, where mutated GCase impacts cellular mechanisms for alpha-synuclein degradation, leading to its aggregation and neuronal cell damage [1]. In Gba1 E326K knock-in mice (a model for increased PD and dementia risk), Gba1 deficiency exacerbates neuroinflammation and promotes pathogenic alpha-synuclein transmission, intensifying disease pathology [3].

In summary, Gba1 is crucial for sphingolipid metabolism, and its dysfunction is closely linked to Gaucher disease and PD. Mouse models, such as the Gba1 E326K knock-in mice, have revealed the role of Gba1 in promoting neuroinflammation and alpha-synuclein-related pathogenesis in PD, enhancing our understanding of the disease mechanisms and potentially guiding new therapeutic strategies [3].

References:

1. Skrahin, Aliaksandr, Horowitz, Mia, Istaiti, Majdolen, Rolfs, Arndt, Zimran, Ari. 2024. GBA1-Associated Parkinson's Disease Is a Distinct Entity. In International journal of molecular sciences, 25, . doi:10.3390/ijms25137102. https://pubmed.ncbi.nlm.nih.gov/39000225/

2. Menozzi, Elisa, Toffoli, Marco, Schapira, Anthony H V. 2023. Targeting the GBA1 pathway to slow Parkinson disease: Insights into clinical aspects, pathogenic mechanisms and new therapeutic avenues. In Pharmacology & therapeutics, 246, 108419. doi:10.1016/j.pharmthera.2023.108419. https://pubmed.ncbi.nlm.nih.gov/37080432/

3. Kweon, Sin Ho, Ryu, Hye Guk, Kwon, Seung-Hwan, Kim, Sangjune, Ko, Han Seok. . Gba1 E326K renders motor and non-motor symptoms with pathological α-synuclein, tau and glial activation. In Brain : a journal of neurology, 147, 4072-4083. doi:10.1093/brain/awae222. https://pubmed.ncbi.nlm.nih.gov/38976650/