Abstract：
:Leucine-rich repeat kinase 2 (LRRK2) is enriched in the striatal projection neurons (SPNs). We found that LRRK2 negatively regulates protein kinase A (PKA) activity in the SPNs during synaptogenesis and in response to dopamine receptor Drd1 activation. LRRK2 interacted with PKA regulatory subunit IIβ (PKARIIβ). A lack of LRRK2 promoted the synaptic translocation of PKA and increased PKA-mediated phosphorylation of actin-disassembling enzyme cofilin and glutamate receptor GluR1, resulting in abnormal synaptogenesis and transmission in the developing SPNs. Furthermore, PKA-dependent phosphorylation of GluR1 was also aberrantly enhanced in the striatum of young and aged Lrrk2(-/-) mice after treatment with a Drd1 agonist. Notably, a Parkinson's disease-related Lrrk2 R1441C missense mutation that impaired the interaction of LRRK2 with PKARIIβ also induced excessive PKA activity in the SPNs. Our findings reveal a previously unknown regulatory role for LRRK2 in PKA signaling and suggest a pathogenic mechanism of SPN dysfunction in Parkinson's disease.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Parisiadou L,Yu J,Sgobio C,Xie C,Liu G,Sun L,Gu XL,Lin X,Crowley NA,Lovinger DM,Cai Hdoi
10.1038/nn.3636subject
Has Abstractpub_date
2014-03-01 00:00:00pages
367-76issue
3eissn
1097-6256issn
1546-1726pii
nn.3636journal_volume
17pub_type
杂志文章abstract：:The CNS, which consists of the brain and spinal cord, is continuously monitored by resident microglia and blood-borne immune cells such as macrophages, dendritic cells and T cells to detect for damaging agents that would disrupt homeostasis and optimal functioning of these vital organs. Further, the CNS must balance b...
journal_title：Nature neuroscience
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pub_type： 杂志文章
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更新日期：2011-03-01 00:00:00
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更新日期：2007-10-01 00:00:00
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pub_type： 杂志文章
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更新日期：2015-05-01 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
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更新日期：2012-09-01 00:00:00
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更新日期：2012-02-26 00:00:00
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pub_type： 已发布勘误
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更新日期：2017-07-01 00:00:00
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更新日期：2016-09-27 00:00:00
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更新日期：2017-03-01 00:00:00
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journal_title：Nature neuroscience
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