α-Synuclein Spreading: Mechanisms and Selective Vulnerability

摘要

Parkinson's disease and its associated synucleinopathies are characterized by the progressive diffusion of abnormally aggregated α-synuclein(α-Syn) in the central nervous system, which is considered to be the central pathological basis for clinical progression of the disease. Although the prion-like intercellular propagation of α-Syn has become a consensus in the field, the molecular mechanism of its specific uptake by neurons and the selective vulnerability of different neural circuits remain key challenges in current research. This review systematically integrates the important findings of recent years and aims to clarify the transmission mechanism of α-Syn and its intervention strategies from a cross-scale perspective ranging from structural biology to translational medicine. In this paper, the structural dynamics of α-Syn from physiological monomer to pathological aggregate were analyzed, and the conformational characteristics of different pathological subtypes(Strains) and their correlation with clinical phenotype were discussed. The subtype specificity may determine the transmission efficiency and cell tropism. Cryoelectron microscopy revealed that there were significant conformational differences in α-Syn fibrils in Parkinson disease and multiple system atrophy, which provided molecular basis for phenotypic heterogeneity. The core of our discussion focuses on the critical step of receptor-mediated endocytosis, positioning pathological α-Syn as a "Trojan horse" that exploits neuronal surface mechanisms. In addition to the classical receptors LAG3, neurexin, and heparan sulfate proteoglycans(HSPGs), we highlight emerging players such as the newly identified candidate receptor TMEM175(a lysosomal potassium channel also implicated in the LRRK2 signaling pathway) and the APOE receptor system associated with genetic risk of disease, which may provide new insights into understanding endocytosis specificity. In addition, we dissect the ongoing debate surrounding the predominant internalization pathways, including macropinocytosis, clathrin-dependent uptake, and the role of tunneling nanotubes(TNTs). Another central theme of this review is deconstructing the selective vulnerability of dopaminergic neurons in the substantia nigra compact. We assessed the convergent effects of cellular and non-cellular autonomic factors. Cellular autonomic factors, such as high metabolic demands, oxidative stress from dopamine metabolism, and lysosomal dysfunction caused by GBA1 mutations, enhance sensitivity to α-Syn toxicity. Non-cellular autonomic factors, on the other hand, are involved in the neuroinflammatory responses of microglia and astrocytes, which release proinflammatory factors through exosomes to accelerate pathological spread. Furthermore, this paper explores how α-Syn aggregates use axonal transport systems(dependent on kinesin and dynein) for bidirectional propagation, and details their transsynaptic propagation pathways by hijacking synaptic vesicle release mechanisms(e.g., interacting with molecules such as VAMP2), thus identifying key "hot spots" within neural circuits. Finally, we translate these mechanistic insights into a critical assessment of current and future therapeutic strategies aimed at stopping the spread of α-Syn. Reflecting on clinical trial failures of monoclonal antibodies such as cinpanemab, it is suggested that targeting specific subtypes or key receptors may yield better efficacy. What's more, small molecular compounds(such as anle 138b) with the function of inhibiting α-Syn oligomer membrane pore formation have shown good preclinical efficacy, and gene therapy strategies such as regulating SNCA expression or enhancing autophagy-lysosomal function are also moving from basic to clinical. The paper concludes by highlighting core controversies in the field, including functional redundancy of endocytic receptors, the causality of pathological propagation, and the role of strain evolution in disease progression. It emphasizes that emerging technologies-such as organoid models derived from human pluripotent stem cells, in vivo single-cell spatial transcriptomics, and AI-assisted protein interaction prediction-will provide critical support for overcoming current research bottlenecks. Ultimately, these advancements will drive the development of disease-modifying therapies targeting specific neural circuits.

关键词

α-synuclein strains / receptor-mediated endocytosis / selective neuronal vulnerability / prion-like propagation