Umaymah Aziz

Introduction. Parkinson’s disease (PD) is a neurodegenerative disorder associated with multiple motor and non-motor symptoms. It has multifactorial pathogenesis and includes complex phenotypes.¹ Heterozygous functional GBA gene variants are one of the most common risk factors associated with Parkinson’s disease.² The GBA gene encodes for glucocerebrosidase, a lysosomal enzyme that is responsible for the breakdown of multiple glycolipids. There are many hypotheses on how precisely mutations in GBA are associated with PD.¹ One notable hypothesis states that the loss of glucocerebrosidase activity leads to a reduced ability to break down alpha-synuclein. Misfolded and aggregated alpha-synuclein are what lead to the formation of Lewy bodies, a pathological hallmark of Parkinson’s disease.²  Methods. Postmortem brain tissue of Parkinson’s patients was assessed for lysosomal enzyme activity via fluorometric assays.³ Liquid chromatography-tandem mass spectrometry of cerebrospinal fluid (CSF) from PD patients was performed to measure glucosylceramide levels.⁴ Mice that carry the entire human alpha-synuclein gene and its regulatory regions (SNCA Tg/Tg) were crossbred with GBA heterozygous knockout mice to assess for pathological changes related to PD. Sectioned brain slices of these mice underwent immunoblot analysis to assess the distribution of phosphorylated alpha-synuclein by using its specific antibody.³ Results. Glucocerebrosidase activity was significantly decreased in the substantia nigra of PD patients with and without GBA variants compared to controls.³ There was a significant increase in glucosylceramide, the direct substrate of glucocerebrosidase, in the CSF of PD patients. The downstream metabolite, sphingomyelin fraction, was found to be significantly decreased in the CSF.⁴  Phosphorylated alpha-synuclein was significantly higher in the brains of double-mutant mice that were crossbred as compared to the brains of SNCA Tg/Tg mice.² Conclusion. The significant increase of glucosylceramide supports the loss of glucocerebrosidase enzyme function hypothesis behind the manifestation of PD in GBA patients.⁴ The heterozygous GBA mutation is proposed to be the reason for the increase in alpha-synuclein as the accumulation of glycolipids, such as glucosylsphingosine, can promote its formation.² Additionally, low levels of alpha-synuclein were found along with an associated glucosylceramide fraction, suggesting that alpha-synuclein is being aggregated into Lewy bodies in these patients.⁴ Ongoing genetic studies have shown that there is a link between specific gene variants and Parkinson’s Disease. Further consolidation on how exactly these variants contribute can be useful in determining how they can be manipulated for a potentially effective treatment option against GBA PD.¹

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2. Ikuno M, Yamakado H, Akiyama H et al. GBA haploinsufficiency accelerates alpha-synuclein pathology with altered lipid metabolism in a prodromal model of Parkinson’s disease. Hum Mol Genet. 2019;28(11):1894-1904. doi:10.1093/hmg/ddz030
3. Moors T, Paciotti S, Ingrassia A et al. Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies. Mol Neurobiol. 2018;56(2):1344-1355. doi:10.1007/s12035-018-1090-0
4. Huh Y, Park H, Chiang M et al. Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson’s disease enrolled in PPMI. NPJ Parkinson’s Dis. 2021;7(1). doi:10.1038/s41531-021-00241-3