Objective: To find out whether GBA deficiency starts at the transcriptional level and if it also involves alternative splicing. To study GBA expression changes in blood of patients with LB diseases and to check if these may be suitable as biomarkers.

Background: Parkinson disease (PD) and dementia with Lewy Bodies (DLB) are Lewy body (LB) diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases.

Methods: The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains, in two areas each, and in blood of 20 DLB patients, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR with transcript-specific primers and sybr-green was used as detection dye. Beta-actin and beta-glucuronidase were used as housekeeping genes in brain, and beta-actin and porphobilinogen deaminase were the housekeeping genes in blood. Expression changes were evaluated by the deltadeltaCt method.

Results: In DLB brain, specific expression profiles were identified in the temporal cortex with the diminution of two of the three tested transcript variants. In PD brains, the caudate nucleus showed decrease of GBA mRNAs.  

In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Of these, early PD patients showed lowest GBA levels which were normal in PD patients with advanced disease. Moreover, GBA mRNA levels were most decreased in early-onset DLB and late-onset PD corresponding in both cases to more aggressive forms of the diseases.

Conclusions: Disease group-specific GBA expression profiles were found in the most affected areas of LB diseases. In blood, GBA expression is diminished in LB diseases, especially in early onset DLB and in early PD patients. Age of disease onset exerted an opposite effect on GBA expression in DLB and PD correlating with disease progression rates. 

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gba-mrna-is-diminished-in-brain-and-blood-of-lewy-body-diseases/