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Abstract
Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients with LB diseases. The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains and in blood of 20 DLB, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR. Expression changes were evaluated by the ΔΔCt method. In brain, specific expression profiles were identified in the temporal cortex of DLB and in the caudate nucleus of PD. In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Early PD and early-onset DLB patients showed lowest GBA levels which were normal in PD patients with advanced disease and DLB patients who developed disease after 70 years of age. In conclusion, disease group specific GBA expression profiles were found in mostly affected areas of LBD. In blood, GBA expression was diminished in LB diseases, especially in patients with early onset DLB and in patients with early PD. Age of disease onset exerts an opposite effect on GBA expression in DLB and PD.
Highlights
Parkinson disease (PD) and dementia with Lewy bodies (DLB) belong to the group of Lewy body diseases (LBDs) and are characterized by abnormal aggregates of alphasynuclein, so called Lewy body pathology (LBP), in the brain [1]
In the present study we have analyzed the differential expression of three GBA transcript variants in the temporal cortex, caudate nucleus and pons of DLB and PD brains divided into pure and common DLB and into
The specific expression profile of GBA transcripts in patients develop dementia (PDD) caudate nucleus showed the decrease of both GBAtv1 and tv5
Summary
Parkinson disease (PD) and dementia with Lewy bodies (DLB) belong to the group of Lewy body diseases (LBDs) and are characterized by abnormal aggregates of alphasynuclein, so called Lewy body pathology (LBP), in the brain [1]. Mutations in the GCase gene GBA cause GCase deficiency leading to glucocerebroside accumulation inside the lysosome. This accumulation results in Gaucher disease, the most frequent lysosomal storage disorder [6]. Deregulation of alternative splicing has been described repeatedly as an important mechanism involved in ageing and disease development [16, 17] In this context, we have reported that differential isoform expression changes are involved in LBD pathogenesis [18, 19]. We wanted to know if GCase deficiency in LBD starts at the transcriptional level; second, if possible brain GBA expression changes are detectable in blood of LBD patients and third, if alternative GBA splicing is dysregulated in these patients
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