Skip to Content
Merck
  • LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.

LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.

Nature neuroscience (2014-01-28)
Loukia Parisiadou, Jia Yu, Carmelo Sgobio, Chengsong Xie, Guoxiang Liu, Lixin Sun, Xing-Long Gu, Xian Lin, Nicole A Crowley, David M Lovinger, Huaibin Cai
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-c-Myc antibody, Mouse monoclonal, clone 9E10, purified from hybridoma cell culture
Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Monoclonal Anti-PSD95 antibody produced in mouse, clone 7E3-1B8, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Monoclonal Anti-Protein Phosphatase 1α antibody produced in mouse, clone PPI-377, ascites fluid
Sigma-Aldrich
Anti-Post Synaptic Density Protein 95 Antibody, clone 7E3-1B8, clone 7E3-1B8, Chemicon®, from mouse
Sigma-Aldrich
Anti-phospho-AMPA Receptor, GluR1 Subunit (pSer845) antibody produced in rabbit, affinity isolated antibody, buffered aqueous glycerol solution
Sigma-Aldrich
Anti-phospho-AMPA Receptor, GluR1 Subunit (pSer831) antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution