NACP/α-synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains

Abstract

The precursor of the non-Abeta component of Alzheimer's disease amyloid (NACP), also called alpha-synuclein, is a major component of Lewy bodies in Parkinson's disease (PD) as well as of neuronal and oligodendroglial cytoplasmic inclusions in multiple system atrophy. We previously reported argyrophilic, tau-negative glial inclusions in the midbrains of patients with PD and have now conducted immunocytochemical and ultrastructural examinations. The PD glial inclusions also are immunoreactive for NACP/alpha-synuclein, but not for beta-synuclein, and ultrastructurally are composed of filamentous structures about 25-40 nm in diameter. Double immunolabeling showed that the inclusions were present in both astrocytic and oligodendroglial cells. They were located within the substantia nigra in 13 of 30 patients with PD and outside the nigra in 24. The number of inclusions was correlated with the severity of nigral neuronal loss. These findings indicate that abnormal accumulation of NACP/alpha-synuclein in glial cells is a pathological feature of PD related to its progression.

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

“…A minority of the LB and LN showed tau immunoreactivity in both individuals, a finding that has been noted in both familial and sporadic cases of Lewy body disease [12,42]. Both had α-synuclein immunoreactive glial cytoplasmic inclusions that are also seen in other familial synucleinopathies and in sporadic PD [17,21,42]. In summary, though the neuropathological changes observed in the two individuals share some characteristics that are consistent with diffuse Lewy body disease (DLB), they exhibit distinguishing characteristics as well.…”

“…Interestingly, some cases of autosomal recessive early onset PD due to PRKN mutations have also been described as having cortical tau pathology [30]. A minority of the LB and LN showed tau immunoreactivity in both individuals, a finding that has been noted in both familial and sporadic cases of Lewy body disease [12,42]. Both had α-synuclein immunoreactive glial cytoplasmic inclusions that are also seen in other familial synucleinopathies and in sporadic PD [17,21,42].…”

Direct Transfer of α-Synuclein from Neuron to Astroglia Causes Inflammatory Responses in Synucleinopathies

“…However, the role of astroglia, the most abundant cell population in the central nervous system, is increasingly evident in these diseases (42,43). In PD and DLB, extensive ␣-synuclein-positive astroglial inclusion bodies have been documented in cortical and subcortical regions (4,6,7). In multiple system atrophy, another synucleinopathy, ␣-synuclein-positive inclusions, called glial cytoplasmic inclusions, are generated in oligodendrocytes (44).…”

“…Formation-Recent studies show that cytoplasmic ␣-synuclein deposition occurs in both neurons and astrocytes in PD (4,6). Considering the fact that astrocytes express no or low levels of ␣-synuclein on their own and are able to take up recombinant ␣-synuclein aggregates from the culture media (34), we hypothesized that neuronal ␣-synuclein aggregates are transmitted to adjacent astrocytes and form pathological inclusion bodies.…”

Involvement of the cerebellum in Parkinson disease and dementia with Lewy bodies

“…10 In the brains of PD and DLB patients, the following alpha-synuclein-immunopositive, insoluble aggregates occur: (1) Lewy bodies (LB) in the neuronal perikarya; (2) Lewy neurites (LN) in neuronal processes; (3) coiled bodies (CB) in oligodendrocytes. 3,[11][12][13] The PD-related brain pathology presumably propagates along neuronal interconnectivities in a prionlike manner and spreads in highly stereotypical temporal and topographical sequences, which were compiled into a neuropathological staging system by Braak et al 2,14 Because DLB patients exhibit similar brain distribution patterns of aggregation pathology as PD patients, it is tempting to suggest that analogous mechanisms of propagation are at work. 12,15,16 Several of the motor symptoms of PD and DLB patients (ie, resting tremor, disturbed balance, gait and postural reflexes), do not respond well to the widely used L-dopa treatment but can be associated with pathological changes in pre-or postcerebellar circuits or the cerebellum itself, which was considered to be unaffected by the aggregation pathology in PD and DLB.…”