The Role of β-synuclein in the Pathological Mechanisms of Dementia with Lewy Bodies
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Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia following Alzheimer’s disease (AD). DLB neuropathology is characterised by Lewy bodies (LBs) and Lewy neurites (LNs) resulting from the modification and aggregation of α-synuclein. The presence of small pre-synaptic accumulations of α-synuclein lead to structural synaptic alterations that may precede neuronal demise. Family member β-synuclein does not readily aggregate and has been shown to prevent α-synuclein aggregation in vitro and in vivo and regional changes in β-synuclein levels has been observed in the brains of DLB patients. α-synuclein pathology is found in the limbic and cortical regions of the DLB brain producing fluctuating cognitive impairment, visual hallucinations and extrapyramidal motor disturbances. In order to examine whether regional changes in β-synuclein influence the course of DLB, examination of protein levels of α-synuclein and β-synuclein in the frontal cortex, occipital cortex and hippocampus of patients with DLB and age-matched controls was performed. Evidence is provided here for a neuronal increase of β-synuclein within the frontal cortex and a decrease in occipital cortex of DLB patients, both regions see similar levels of oligomeric α-synuclein. Further examination of key pre-synaptic SNARE proteins reveal an increase of VAMP2 in the frontal cortex and a decrease of VAMP2 and SNAP25 in the occipital cortex. Autophagy markers LC3-II and p62 were also increased in the frontal cortex where an increase in β-synuclein was identified in DLB brains and in vitro overexpression of β-synuclein attenuates the autophagy flux. Collectively, this data suggests that β-synuclein changes in the DLB cortex are regionally distinct and the possibility that β-synuclein may exacerbate neuronal dysfunction by influencing protein degradation pathways, cannot be excluded. This data highlights the possibility of a dual role for β-synuclein that may be both protective and antagonistic, advocating caution when considering the use of β-synuclein as a potential therapeutic.
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