The decrease of β-synuclein in cortical brain areas defines a molecular subgroup of dementia with Lewy bodies

Lewy body diseases include dementia with Lewy bodies and Parkinson's disease. Whereas dementia with Lewy bodies and Parkinson's disease can be distinguished as separate clinical entities, the pathological picture is very often identical. alpha-synuclein aggregation is a key event in the pathogenesis of Lewy body diseases and beta-synuclein inhibits alpha-synuclein aggregation in vitro and in vivo. Recently, beta-synuclein has been shown to interact directly with alpha-synuclein, regulating its functionality and preventing its oligomerization. In this study, we analysed the expression of two beta-synuclein transcript variants and the main alpha-synuclein transcript SNCA140, in frozen samples of three areas from brains of patients with (i) pure diffuse Lewy body pathology; (ii) pure Alzheimer's disease pathology; (iii) diffuse Lewy body pathology and concomitant Alzheimer's disease pathology and (iv) controls. Relative messenger RNA expression was determined by real-time polymerase chain reaction, expression changes were evaluated by the Delta Delta C-t method and messenger RNA expression data were confirmed at the protein level. A drastic diminution of beta-synuclein expression was observed in cortical areas of all samples that presented neuropathological features corresponding to pure diffuse Lewy body pathology and the clinical phenotype of dementia with Lewy bodies, but not in those with neuropathological features corresponding to diffuse Lewy body pathology and concomitant Alzheimer's disease pathology or the clinical phenotype of Parkinson's disease with dementia. The correlation of expression data with the clinical phenotype and neuropathological diagnosis of the patients suggested the existence of a specific molecular subtype of dementia with Lewy bodies, characterized by a strong decrease of beta-synuclein in the frontal and temporal cortices. Furthermore, our findings provide new insights into the pathogenesis of Lewy body diseases that may be important for the understanding of molecular mechanisms involved in these complex diseases.