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Pale neurites, premature α-synuclein aggregates with centripetal extension from axon collaterals.

ABSTRACT: Progressive aggregation of α-synuclein (αS) from pale bodies (PBs) and extension from Lewy neurites (LNs) are candidate mechanisms for Lewy body (LB) formation. To identify how aggregation of αS is related to its extension along neurites, 60-µm-thick brainstem sections of Parkinson disease (PD) patients were prepared for three-dimensional (3D) reconstruction of αS-positive neurites with neurofilament (NF) and thiazin red (TR), a fluorochrome with an affinity to solid aggregates. This demonstrated 3D layering of αS surrounded by NF with the aggregates probed by TR in the center, corresponding to the eosinophilic core of mature LBs. This eosinophilic/TR-positive profile, characteristically absent in PBs, premature counterpart of LBs, was similarly absent in some LNs. We would like to refer these premature LNs as "pale neurites" (PNs). Their premature nature was evidenced by 3D fluoroprofiling with quantum dots (QDs) and subsequent electron microscopic identification (3D-oriented immunoelectron microscopy) as loosely packed αS (QDs)-positive filaments. Quantification of LNs, frequently extended around branching axons, demonstrated that LNs are initiated at axon collaterals to extend centripetally into proximal segments. This branching-oriented extension of αS is related to its selective predisposition to systems with highly divergent axons, preferentially affected in PD, which may explain barely somatotopic manifestations of PD.

SUBMITTER: Kanazawa T

PROVIDER: S-EPMC8029413 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Parkinson's disease (PD) is characterized neuropathologically by intracellular aggregates of fibrillar α-synuclein, termed Lewy bodies (LBs). Approximately 90% of α-synuclein deposited as LBs is phosphorylated at Ser129 in brains with PD. In contrast, only 4% of total α-synuclein is phosphorylated at Ser129 in brains with normal individuals. It is unclear why extensive phosphorylation occurs in the pathological process of PD. To address this issue, we investigated a mechanism and role of Ser129-phosphorylation in regulating accumulation of α-synuclein. In CHO cells, the levels of Ser129-phosphorylated soluble α-synuclein were maintained constantly to those of total α-synuclein in intracellular and extracellular spaces. In SH-SY5Y cells and rat primary cortical neurons, mitochondrial impairment by rotenone or MPP+ enhanced Ser129-phosphorylation through increased influx of extracellular Ca2+. This elevation was suppressively controlled by targeting Ser129-phosphorylated α-synuclein to the proteasome pathway. Rotenone-induced insoluble α-synuclein was also targeted by Ser129-phosphoryation to the proteasome pathway. Experiments with epoxomicin and chloroquine showed that proteasomal targeting of insoluble Ser129-phosphorylated α-synuclein was enhanced under lysosome inhibition and it reduced accumulation of insoluble total α-synuclein. However, in a rat AAV-mediated α-synuclein overexpression model, there was no difference in the number of total α-synuclein aggregates between A53T mutant and A53T plus S129A double mutant α-synuclein, although Ser129-phosphorylated α-synuclein-positive aggregates were increased in rats expressing A53T α-synuclein. These findings suggest that Ser129-phosphorylation occurs against stress conditions, which increases influx of extracellular Ca2+, and it prevents accumulation of insoluble α-synuclein by evoking proteasomal clearance complementary to lysosomal one. However, Ser129-phosphorylation may provide an ineffective signal for degradation-resistant aggregates, causing extensive phosphorylation in aggregates.

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Pale neurites, premature α-synuclein aggregates with centripetal extension from axon collaterals.

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