Accumulation of phosphorylated α‐synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration

Abstract

The histological hallmark of multiple system atrophy (MSA) is accumulation of phosphorylated α-synuclein in oligodendrocytes. However, it is uncertain whether phosphorylated α-synuclein accumulates in astrocytes of MSA patients. We immunohistochemically examined the frontal and temporal lobes, basal ganglia, cerebellum, brainstem and spinal cord of patients with MSA (n = 15) and Lewy body disease (n = 20), and also in control subjects (n = 20). Accumulation of abnormally phosphorylated and aggregated α-synuclein was found in subpial and periventricular astrocytes in six of the 15 patients with MSA (40%). The structures were confined to the subpial surface of the ventro-lateral part of the spinal cord and brainstem, as well as the subependymal region of the lateral ventricles. They were not visualized by Gallyas-Braak staining, and were immunonegative for ubiquitin and p62. Immunoelectron microscopy revealed that the phosphorylated α-synuclein-immunoreactive structures in astrocytes were non-fibrillar and associated with granular and vesicular structures. The extent of phosphorylated α-synuclein-immunoreactive astrocytes was correlated with disease duration. No such structures were found in Lewy body disease or controls. Accumulation of phosphorylated α-synuclein can occur in subpial and periventricular astrocytes in patients with MSA, especially in those with a long disease duration.

α‐synuclein astrogliopathy: A possible specific feature in α‐synucleinopathy

“…Similar to previous research, 1 the accumulation of α-synuclein in subpial or perivascular astrocytes in the striatum were observed in 11% (16/140) of MSA patients (Table 1). Numerous TSAs were observed around the lenticulostriate arteries (Fig.…”

“…1 The authors revealed that this finding is specific for MSA patients and possibly related with a long disease duration. The morphology and location of this astrocytic pathology are reminiscent of aging-related tau astrogliopathy (ARTAG), which is characterized by thorn-shaped astrocytes (TSA) or granular/fuzzy astrocytes in subependymal, subpial, perivascular, gray matter, and white matter regions.…”

Recent advances in neuropathology, biomarkers and therapeutic approach of multiple system atrophy

“…Nakamura et al reported that these astrocytes were a specific feature of MSA, and that they correlated with disease duration 20. Subsequently, Koga et al found α-synuclein-positive astrocytes in subpial and perivascular regions in both MSA (figure 2P) and Lewy body disease, suggesting this pathology is not a specific feature of MSA 21…”

The neuropathology of multiple system atrophy and its therapeutic implications

“…Both astrogliosis and microgliosis have been observed in MSA brains (Schwarz et al, 1996), and in transgenic mouse models of MSA (Ubhi et al, 2012; Valera et al, 2015; Valera et al, 2014). As-trocytes are able to accumulate α-syn in MSA and in tg mouse models (Mandler et al, 2015; Nakamura et al, 2016), and stimulate the release of pro-inflammatory cytokines (Lee et al, 2010). MSA brains exhibit widespread astrogliosis (Schwarz et al, 1996) correlated to the presence of nearby GCI-positive oligodendrocytes (Radford et al, 2015), suggesting that localized presence of extracellular α-syn may underlie the astrocytic pathology in MSA.…”