期刊
FEBS OPEN BIO
卷 11, 期 2, 页码 354-366出版社
WILEY
DOI: 10.1002/2211-5463.13060
关键词
dopaminergic neuron; human‐ induced pluripotent stem cell; PARK4; Parkinson' s disease; SNCA triplication; α ‐ synuclein
资金
- Japan Agency for Medical Research and Development (AMED) [JP17mk0104027, JP20bm0204001, JP20bm0804024]
- Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation (NIBIO)
- JSPS KAKENHI [JP17K16136]
- Brain Mapping by Integrated Neuroethologies for Disease Studies (Brain/MINDS) from AMED [JP18ek0109195, JP20dm0207070]
- Research Center Network for Realization Research Centers/Projects of Regenerative Medicine (the Program for Intractable Disease Research Utilizing Disease-specific iPS Cells and the Acceleration Program for Intractable Diseases Research Utilizing Disease-s
- Practical Research Project for Rare/Intractable Diseases from AMED [16ek0109013h0003, 16ek0109158h0002, 16bm0609003h0005, 17bm0804003h0001, 18bm0804003h0002, 19bm0804003h0003]
- grants for Keio University Global Initiative Research Projects
- Practical Research Project for Rare/Intractable Diseases
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.
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.
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