Richard M. Meade

α-synuclein (αS) aggregation and propagation are central features of Parkinson’s disease pathology. Preformed fibril (PFF) models have shown that extracellular αS aggregates can enter neurons and seed aggregation of endogenous αS. Within the brain, these seeds also encounter microglia and astrocytes, which efficiently internalise fibrillar αS and can influence its subsequent fate. This review examines the mechanisms through which glial cells take up, process, degrade and redistribute extracellular αS seeds. When lysosomal trafficking and degradation are effective, glia can act as a sink for seed-competent αS and restrict neuronal seeding and propagation. In contrast, lysosomal dysfunction, incomplete proteolysis or excessive aggregate burden can promote persistence, modification and redistribution of seed-competent αS, including through extracellular vesicles and intercellular transfer. Evidence from microglial and astrocytic models therefore indicates that the outcome of glial uptake depends on the balance between internalisation, intracellular processing and subsequent release. Differences in αS conformation, fibril preparation, inflammatory state, genetic background and experimental model may further explain the apparently protective and pathogenic effects of glia reported across different studies. Understanding the factors that determine whether glial uptake results in productive clearance or continued propagation may identify therapeutic strategies that enhance the removal of pathogenic αS without broadly suppressing glial function.

Preventing the aggregation of α-synuclein (αS) into toxic oligomers and conformers is a major therapeutic goal in conditions such as Parkinson’s disease and Lewy body dementia. However, the large intracellular protein–protein interfaces within such aggregates make this a challenging target for small molecule approaches or biologics, which often lack cell permeability. Peptides occupy a suitable middle ground and are increasingly being explored as preventative treatments. We previously showed that the N-terminal lipid binding region (αS_1–25) inhibits αS aggregation. Building on this, we designed a series of N- and C-terminal truncations to systematically reduce the peptide length, enabling a 56% downsizing (i.e., truncating 92% of the full-length αS protein), to identify the smallest functional unit capable of binding αS and potently blocking its aggregation and toxicity. We next introduced seven systematic i → i + 4 helix constraints to assess impact on (i) α-helicity, (ii) aggregation inhibition, (iii) serum stability, (iv) neuronal uptake, and (v) phenotypic rescue. This work maps key amphipathic features and identifies residues that are critical for αS engagement and inhibitory activity. The most effective helix-constrained peptide, αS_2–12(L6), showed marked improvements across all metrics and represents a strong candidate for further therapeutic development.

Alpha-synuclein (αS) is the major constituent of Lewy bodies and a pathogenic hallmark of all synucleinopathathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). All diseases are determined by αS aggregate deposition but can be separated into distinct pathological phenotypes and diagnostic criteria. Here we attempt to reinterpret the literature, particularly in terms of how αS structure may relate to pathology. We do so in the context of a rapidly evolving field, taking into account newly revealed structural information on both native and pathogenic forms of the αS protein, including recent solid state NMR and cryoEM fibril structures. We discuss how these new findings impact on current understanding of αS and PD, and where this information may direct the field.