Jon Douglas (@atranscendedman.bsky.social)

Alpha-synuclein at the crossroads of host–virus interactions: immunological roles beyond the nervous system | Journal of Virology Alpha-synuclein (hereafter, abbreviated as α-syn) is a small, intrinsically disordered protein predominantly localized at presynaptic terminals in the central nervous system (CNS). Endowed with structural plasticity, it is involved in key aspects of synaptic physiology, including regulation of synaptic vesicle trafficking, modulation of neurotransmitter release, and maintenance of synaptic plasticity. In detail, α-syn acts as a molecular chaperone for SNARE complex assembly, thereby facilitating efficient neurotransmission and contributing to the fine-tuning of neuronal connectivity (1). Although its mechanisms of action remain to be fully elucidated, the physiological presence of α-syn is generally regarded as essential for synaptic homeostasis and normal neuronal function (2). The same structural and functional properties that enable α-syn to support neurotransmission, however, may also render it vulnerable to maladaptive conformational changes, thereby linking its normal biology to potential pathogenic processes. Indeed, the pathological significance of α-syn has been firmly established in Parkinson’s disease (PD) and related synucleinopathies (2). Misfolding and aggregation of α-syn lead to the formation of insoluble fibrillar inclusions known as Lewy bodies and Lewy neurites, which are pathological hallmarks of PD. Lewy bodies and Lewy neurites are intracellular inclusions enriched in aggregated α-syn species, frequently phosphorylated at Ser129 (pSer129 α-syn), together with other proteins and membranous components, and are widely used as neuropathological correlates of synucleinopathy. These aggregates disrupt cellular proteostasis, impair mitochondrial and lysosomal function, and ultimately contribute to neurodegeneration. Moreover, abnormal α-syn species are thought to propagate in a prion-like manner across neuronal and systemic networks, thereby driving disease progression and accounting for the stereotypical spatiotemporal distribution of pathology in PD. Thus, α-syn embodies a paradoxical duality, functioning as a critical regulator of synaptic biology under physiological conditions, while acting as a central pathogenic effector in the context of neurodegenerative disease (3). https://journals.asm.org/doi/10.1128/jvi.00191-26