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

Abstract

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. α-synuclein aggregation is a key event in the pathogenesis of Lewy body diseases and β-synuclein inhibits α-synuclein aggregation in vitro and in vivo. Recently, β-synuclein has been shown to interact directly with α-synuclein, regulating its functionality and preventing its oligomerization. In this study, we analysed the expression of two β-synuclein transcript variants and the main α-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 ΔΔC(t) method and messenger RNA expression data were confirmed at the protein level. A drastic diminution of β-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 β-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.

New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases

“…Previous studies of ours have shown that in FC the main transcript (SNCA140) is diminished in pure DLB and does not show important changes in common DLB [13]. Recently, we have also reported that brains with pure LBP from patients with relative short duration of DLB lack BS expression in cortical regions, especially in TC [20]. Part of our present data underline these results showing the drastic diminution of all SNCB transcripts in the cortex of G-pDLB.…”

“…Since high-quality RNA cannot be taken for granted when dealing with PM brain samples [30], we assessed SNCB isoform, human neuron-specific enolase 2 (NSE), and synaptophysin (SYP) mRNA degradation rates in order to assure that they presented similar stabilities even at RIN values of about 6 as described before [20].…”

“…Moreover, the findings of a previous study on SNCB expression led us to divide patients with neuropathologic diagnosis of diffuse LBP by correlating clinico-pathological data [20]. Therefore, the results of this study were also analyzed in the following groups: (1) samples with neuropathological features corresponding to pure LBP and with the clinical phenotype of DLB (G-pDLB); (2) samples with neuropathological features corresponding to common LBP and with the clinical phenotype of DLB (G-cDLB); (3) samples with neuropathological diagnosis of pure or common LBP, both with the clinical phenotype of PDD (G-PDD); (4) the AD group, with coinciding neuropathological and clinical manifestation of AD; and (5) normal controls (Table 1).…”

“…Accordingly, BS is able to inhibit AS aggregation in vitro [17,18] and double transgenic mice expressing both human AS and BS show diminished inclusion body formation [19]. Moreover, we have recently shown that BS expression is drastically diminished in a molecular subgroup of DLB corresponding to cases that clinically presented as DLB with short disease duration and showed pure LB pathology [20].…”

Influence of Lentiviral β-Synuclein Overexpression in the Hippocampus of a Transgenic Mouse Model of Alzheimer's Disease on Amyloid Precursor Protein Metabolism and Pathology

“…So far it is known that equimolar β-Syn protein concentrations inhibit Aβ fibril formation in vitro [24]. Decreased β-Syn mRNA levels were found in AD patients compared to healthy controls [2,50,51]. Consequently, we have investigated the effects of wt β-Syn in a tg animal model of AD (APP SL animals) over a distinct time period.…”