Abstract
Multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) are α-synucleinopathies that exhibit widespread astrogliosis as a component of the neuroinflammatory response. Munc18, a protein critical to vesicle exocytosis, was previously found to strongly mark morphologically activated astrocytes in brain tissue of MSA patients. Immunofluorescence of MSA, DLB and normal brain tissue sections was combined with cell culture and co-culture experiments to investigate the relationship between extracellular α-synuclein and the transition to a secretory astrocyte phenotype. Increased Munc18-positive vesicles were resolved in activated astrocytes in MSA and DLB tissue compared to controls, and they were also significantly upregulated in the human 1321N1 astrocytoma cell line upon treatment with α-synuclein, with parallel increases in GFAP expression and IL-6 secretion. In co-culture experiments, rat primary astrocytes pretreated with α-synuclein inhibited the growth of neurites of co-cultured primary rat neurons and upregulated chondroitin sulphate proteoglycan. Taken together, these results indicate that the secretory machinery is significantly upregulated in the astrocyte response to extracellular α-synuclein and may participate in the release of neuroinhibitory and proinflammatory factors in α-synucleinopathies.
Highlights
Abnormal aggregates of alpha-synuclein (α-syn) constitute the common histopathological hallmark of neurodegenerative disorders such as Parkinson’s disease (PD), multiple systems atrophy (MSA)and dementia with Lewy bodies (DLB); all grouped as α-synucleinopathies [1,2,3,4]
Rat primary astrocytes pretreated with α-synuclein inhibited the growth of neurites of co-cultured primary rat neurons and secreted chondroitin sulphate proteoglycan (CSPG)
Extracellular α-syn is a potent mediator of astrocyte activation and may lead to upregulation of Extracellular is a potentof mediator of astrocyte activationwhich and may to an upregulation the secretory pathwayα-syn and secretion neuroinhibitory molecules, canlead play importantofrole in the secretory pathway and secretion of neuroinhibitory molecules, which can play an important role the the pathogenesis of α-synucleinopathies, including Multiple system atrophy (MSA) and DLB [13]
Summary
Abnormal aggregates of alpha-synuclein (α-syn) constitute the common histopathological hallmark of neurodegenerative disorders such as Parkinson’s disease (PD), multiple systems atrophy (MSA)and dementia with Lewy bodies (DLB); all grouped as α-synucleinopathies [1,2,3,4]. Abundant as disordered monomer or alpha-helical tetramer in the presynaptic region of neurons [5], α-syn is a protein that, for reasons yet unknown, misfolds as oligomers, fibrils and protofibrils; which are major components of intracellular inclusion bodies known as Lewy bodies (LBs), Lewy neurites (LNs) or glial cytoplasmic inclusions (GCIs) [6,7]. The direct action of α-syn on astrocytes is known to induce changes of morphology, transcription of target genes and secretion of proinflammatory cytokines that characterize neuroinflammation [11,12,13,14]. This process involves, but is not restricted to, stimulation (in microglia) or. Phosphorylation of p38 MAPK and JNK [17], and nuclear translocation of NF-κB in B-cells are some of the signaling pathways affected; with the induction of proinflammatory factors, such as Cox-2, iNOS, TNF-α, Il-1ß and IL-6 [18,19]
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