Alpha-synuclein dynamics in induced pluripotent stem cell-derived dopaminergic neurons from a Parkinson's disease patient (PARK4) with SNCA triplication

Parkinson's disease (PD) is a neurodegenerative disorder caused by the selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Lewy bodies (LBs), another histological hallmark of PD, are observed in patients with familial or sporadic PD. The therapeutic potential of reducing the accumulation of alpha-synuclein, a major LB component, has been investigated, but it remains unknown whether the formation of LBs results in the loss of DA neurons. PARK4 patients exhibit multiplication of the alpha-synuclein gene (SNCA) without any pathological mutations, but their symptoms develop relatively early. Therefore, study of PARK4 might help elucidate the mechanism of alpha-synuclein aggregation. In this study, we investigated the dynamics of alpha-synuclein during the early stage of immature DA neurons, which were differentiated from human-induced pluripotent stem cells (hiPSCs) derived from either a PARK4 patient with SNCA triplication or a healthy donor. We observed increased alpha-synuclein accumulation in PARK4 hiPSC-derived DA neurons relative to those derived from healthy donor hiPSCs. Interestingly, alpha-synuclein accumulation disappeared over time in the PARK4 patient-derived DA neurons. Moreover, an SNCA-specific antisense oligonucleotide could reduce alpha-synuclein levels during the accumulation stage. These observations may help reveal the mechanisms that regulate alpha-synuclein levels, which may consequently be useful in the development of new therapies for patients with sporadic or familial PD.

Automated summary

This study found increased accumulation of alpha-synuclein in DA neurons derived from PARK4 patients, but the accumulation disappeared over time. An SNCA-specific antisense oligonucleotide could reduce alpha-synuclein levels during the accumulation stage.