Evolving insights into erythrocytes in synucleinopathies

Synucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are characterized by neuronal loss accompanied by α-synuclein (α-syn) accumulation in the brain. While research conventionally focused on brain pathology, there is growing interest in peripheral alterations. Erythrocytes, which are rich in α-syn, have emerged as a compelling site for synucleinopathies-related alterations. Erythrocyte-derived extracellular vesicles (EVs), containing pathological α-syn species, can traverse the blood-brain barrier (BBB) under certain conditions and the gastrointestinal tract, where α-syn and gut microbiota interact extensively. This review explores the accumulating evidence of erythrocyte involvement in synucleinopathies, as well as their potential in disease pathogenesis and diagnosis. Given their unique properties, erythrocytes and erythrocyte-derived EVs may also serve as an ideal therapeutic platform for treating synucleinopathies and beyond.