Abstract
Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by aggregation of α-synuclein in oligodendrocytes to form glial cytoplasmic inclusions. According to the distribution of neurodegeneration, MSA is subtyped as striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), or as combination of these 2 (mixed MSA). In the current study, we aimed to investigate regional microglial populations and gene expression in the 3 different MSA subtypes. Microscopy with microglial marker Iba-1 combined with either proinflammatory marker CD68 or anti-inflammatory marker Arginase-1 was analyzed in control, SND, and OPCA cases (n = 5) using paraffin embedded sections. Western immunoblotting and cytokine array were used to determine protein expression in MSA and control brain regions. Gene expression was investigated using the NanoString nCounter Human Inflammation panel v2 mRNA Expression Assay. Analysis of neuropathological subtypes of MSA demonstrated a significant increase in microglia in the substantia nigra of OPCA cases. There was no difference in the microglial activation state in any region. Cytokine expression in MSA was comparable with controls. Decreased expression of CX3CL1 precursor protein and significantly greater CX3CR1 protein was found in MSA. NanoString analysis revealed the >2-fold greater expression of ARG1, MASP1, NOX4, PTGDR2, and C6 in MSA.
Highlights
Multiple system atrophy (MSA) is a sporadic adultonset progressive neurodegenerative disease characterized clinically by parkinsonism, cerebellar ataxia, and autonomic failure
We demonstrated a significant increase in total microglial number in the substantia nigra of olivopontocerebellar atrophy (OPCA) cases (p 1⁄4 0.009), the number of microglia in striatonigral degeneration (SND) substantia nigra approached a significant increase in MSA but the p value lacked significance when adjusted for multiple comparisons (p 1⁄4 0.08)
There was no significant difference in the number of microglia in MSA frontal lobe (SND p 1⁄4 0.26, OPCA p 1⁄4 0.43) or cerebellar white matter compared with control (SND p 1⁄4 0.99, OPCA p 1⁄4 0.87) when the p values were adjusted for multiple comparisons (Fig. 1A-C)
Summary
Multiple system atrophy (MSA) is a sporadic adultonset progressive neurodegenerative disease characterized clinically by parkinsonism, cerebellar ataxia, and autonomic failure. We have previously shown that microglia, the key cellular component of the neuroinflammatory response, are increased in number in a group of MSA cases with mixed neuropathological subtypes [8]. Microglia had generally been proposed to have a bipolar activation style and in the absence of insult, toxin, or disease, they exist in a ramified state. In their ramified state, microglia have constantly motile processes surveying their local area [11]. Microglial processes may detect different inducers that can stimulate the cells to become activated either to a proinflammatory, phagocytic (M1 state), an anti-inflammatory, prohealing (M2 state), or a “resolution phase macrophage” (rM), which has hybrid
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