Internalized SNCA/α-synuclein fibrils become truncated and resist degradation in neurons while glial cells rapidly degrade SNCA fibrils.

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Parkinson disease (PD) and other α-synucleinopathies are characterized by the intracellular aggregates of SNCA/α-synuclein (synuclein, alpha) thought to spread via cell-to-cell transmission. To understand the contributions of various brain cells to the spreading of SNCA pathology, we examined the metabolism of SNCA aggregates in neuronal and glial cells. In neurons, while the full-length SNCA rapidly disappeared following SNCA pre-formed-fibril (PFF) uptake, truncated SNCA accumulated with a half-life of days rather than hours. Epitope mapping and fractionation studies indicate that SNCA fibrils internalized by neurons were truncated at the C-terminal region and remained insoluble. In contrast, microglia and astrocytes rapidly metabolized SNCA fibrils as the half-lives of SNCA fibrils in these glial cells were Abbreviations: 3MA, 3-methyladenine; aa, amino acids; AF, Alexa Fluor; Baf A1, bafilomycin A1; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethyl sulfoxide; FL, full-length; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMM, high molecular mass; Hs, human; kDa, kilodalton; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; ML, molecular layer; NAC domain, non-amyloidal component; PCN, primary cortical neuron; PD, Parkinson diseases; PFF, pre-formed-fibril; PFF-488, PFF Alexa Fluor-488; PMG, primary microglia; SNCA, synuclein, alpha; SNCA[∆], C-terminally truncated SNCA; SQSTM1/p62, sequestosome 1; TX-100, Triton X-100.

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