期刊
SCIENCE SIGNALING
卷 10, 期 493, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aal4165
关键词
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资金
- Swedish Research Council [2011-3116, 2011-3318, 2016-01526]
- Swedish Foundation for Strategic Research
- European Commission
- Cancerfonden [CAN 2016/572]
- Hjarnfonden [FO2015:0202]
- Parkinsonfonden
- Karolinska Institutet (SFO Thematic Center in Stem cells and Regenerative Medicine)
- Vinnova [2016-01526] Funding Source: Vinnova
- Swedish Research Council [2016-01526] Funding Source: Swedish Research Council
Parkinson's disease (PD) is a neurodegenerative disorder in which the loss of dopaminergic neurons in the midbrain (mDA neurons) causes progressive loss of motor control and function. Using embryonic and mDA neurons, midbrain tissue from mice, and differentiated human neural stem cells, we investigated the mechanisms controlling the survival of mDA neurons. We found that the extracellular matrix protein laminin-511 (LM511) promoted the survival and differentiation of mDA neurons. LM511 bound to integrin alpha(3)beta(1) and activated the transcriptional cofactor YAP. LM511-YAP signaling enhanced cell survival by inducing the expression of the microRNA miR-130a, which suppressed the synthesis of the cell death-associated protein PTEN. In addition, LM511-YAP signaling increased the expression of transcription factors critical for mDA identity, such as LMX1A and PITX3, and prevented the loss of mDA neurons in response to oxidative stress, a finding that warrants further investigation to assess therapeutic potential for PD patients. We propose that by enhancing LM511-YAP signaling, it may be possible to prevent mDA neuron degeneration in PD or enhance the survival of mDA neurons in cell replacement therapies.
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