LRRK2 regulates synaptogenesis and dopamine receptor activation through modulation of PKA activity.
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.
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [3].
Loukia
L
Parisiadou
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Department of Geriatrics, Beijing Geriatric Hospital, Beijing, China. [3].
Jia
J
Yu
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2].
Carmelo
C
Sgobio
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Chengsong
C
Xie
1] Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA. [2] Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Guoxiang
G
Liu
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Lixin
L
Sun
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Xing-Long
XL
Gu
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Xian
X
Lin
Laboratory of Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, Maryland, USA.
Nicole A
NA
Crowley
Laboratory of Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, US National Institutes of Health, Rockville, Maryland, USA.
David M
DM
Lovinger
Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.
Huaibin
H
Cai
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit / Q000096:biosynthesis / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism* / Q000473:pathology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; C583261:Drd1 protein, mouse; D017447:Receptors, Dopamine D1; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases