Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson's Disease

Abstract

Parkinson's disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.

Keywords: Parkinson’s disease progression; autophagy-lysosomal pathway; biomarker; degradation; α-syn exosomal secretion.

FIGURE 1

Crosstalk between the autophagy-lysosomal pathway (ALP) and the exosomes secretion in Parkinson’s disease. (A) The presence of soluble free or exosomes-containing α-synuclein (α-syn) derived from Substantia Nigra can be detected in cerebrospinal fluid (CSF) and blood samples from Parkinson’s disease patients, potentially contributing to the early disease’s diagnosis and progression monitoring. (B) Overview of the autophagy-lysosomal pathway (ALP) and exosomes secretion. In (1), the formation of the initial membrane that will originate the double-vesicle autophagosome (2) depends on several complex proteins’ actions (shown in different colors). (3) The fusion of autophagosomes with lysosomes is a final step of the pathway, originating the autolysosome (4), where the substrates are finally degraded into their monomeric components that can be recycled back to the cytosol (5). Multivesicular bodies (MVB) originate the exosomes vesicles, which are secreted by exocytosis and participate in the cell-to-cell transmission of α-syn (neurons and glia cells).

FIGURE 2

Contribution of autophagy-lysosomal pathway and α-syn secreted in Parkinson’s disease. (A) In normal conditions, it is possible to detect monomers of alpha-synuclein (α-syn), which are degraded by Ubiquitin Proteasome System (UPS), and oligomers of α-syn are efficiently degraded by Autophagy-Lysosomal (ALP) pathway or can be secreted by exosomes. Both degradation and secretion processes occur in a coordinate balance. (B) On Parkinson’s Disease condition, abundant oligomers and fibrils of α-syn are formed, and it less degraded by autophagy due to an impairment of this pathway, and it is possible to observe an increased secretion of α-syn by exosomes.