Pathway-specific deregulation of striatal excitatory synapses in LRRK2 mutations

Chen, Chuyu; Soto, Giulia; Bannon, Nicholas M.; Kang, Shuo; Kozorovitskiy, Yevgenia; Parisiadou, Loukia

doi:10.1101/2020.01.03.894410

Cited by 2 publications

(3 citation statements)

References 58 publications

(91 reference statements)

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“…We speculate that PKA signaling at the striatal level may be dysregulated due to RC mutation [64,65] . This is in line with our finding that increased synaptic PKA activities are observed only in RC and not GS striatal synaptic fractions [15,66] To our knowledge, this study is the first to examine evoked dopamine release in the RC KI mice. Our results are at odds with an earlier report that measured basal dopamine content in RC KI mice and found no changes using bulk tissue HPLC, which lacks the spatial and temporal resolution that fast-scanning cyclic voltammetry offers [20] .…”

Section: Discussion (851 Words)supporting

confidence: 91%

“…targets downstream Rab proteins that are involved in vesicular trafficking to the plasma membrane and direct neurotransmitter release [12,71] . Specifically, we recently demonstrated that RC mutation resulted in higher phosphorylation of Rab8A-a downstream LRRK2 substrate-in synaptic striatal extracts, compared to GS mutation [15] . In addition, the LRRK2 RC mutation leads to a synaptic translocation and dysregulation of excitatory synaptogenesis and transmission via an increased PKA-mediated regulation of GluR1 in SPNs [66] .…”

Section: Discussion (851 Words)mentioning

confidence: 99%

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Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

Xenias¹,

Chen²,

Kang³

et al. 2020

Preprint

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LRRK2 mutations are associated with both familial and sporadic forms of Parkinson’s disease (PD). Convergent e vidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations—G2019S and R1441C—we investigated how pathogenic LRRK2 mutations altered striatal physiology. We found that R1441C mice displayed a reduced nigrostriatal dopamine release and hypoexcitability in indirect-pathway striatal projection neurons. These alterations were associated with impaired striatal-dependent motor learning in the R1441C knock-in mice. In contrast, no detectable alterations were observed in the G2019S knock-in mice. In summary, our data argue that the impact of individual LRRK2 mutations cannot be simply generalized. Our findings have far-reaching implications for devising treatment strategies for PD patients.

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Section: Discussion (851 Words)supporting

confidence: 91%

Section: Discussion (851 Words)mentioning

confidence: 99%

Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

Xenias¹,

Chen²,

Kang³

et al. 2020

Preprint

Self Cite

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“…In addition to SPNs of the direct and indirect pathways, LRRK2 is strongly expressed in eccentric SPNs, which express both D1Rs and D2Rs [ 56 ]. As discussed in the following sections, despite similar expression in direct and indirect-pathway SPNs, the phenotypes manifested by LRRK2 mutation differ between the two pathways [ 58 , 59 ], likely due to interactions with differentially modulated signaling pathways, including PKA. PKA signaling is oppositely affected by dopamine in the direct and indirect pathways [ 60 ].…”

Section: Cell-type Specificity Of Lrrk2 Expressionmentioning

confidence: 99%

LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights

Skelton

Tokars

Parisiadou

2022

Cells

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Mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson’s disease with a similar clinical presentation and progression to idiopathic Parkinson’s disease, and common variation is linked to disease risk. Recapitulation of the genotype in rodent models causes abnormal dopamine release and increases the susceptibility of dopaminergic neurons to insults, making LRRK2 a valuable model for understanding the pathobiology of Parkinson’s disease. It is also a promising druggable target with targeted therapies currently in development. LRRK2 mRNA and protein expression in the brain is highly variable across regions and cellular identities. A growing body of work has demonstrated that pathogenic LRRK2 mutations disrupt striatal synapses before the onset of overt neurodegeneration. Several substrates and interactors of LRRK2 have been identified to potentially mediate these pre-neurodegenerative changes in a cell-type-specific manner. This review discusses the effects of pathogenic LRRK2 mutations in striatal neurons, including cell-type-specific and pathway-specific alterations. It also highlights several LRRK2 effectors that could mediate the alterations to striatal function, including Rabs and protein kinase A. The lessons learned from improving our understanding of the pathogenic effects of LRRK2 mutations in striatal neurons will be applicable to both dissecting the cell-type specificity of LRRK2 function in the transcriptionally diverse subtypes of dopaminergic neurons and also increasing our understanding of basal ganglia development and biology. Finally, it will inform the development of therapeutics for Parkinson’s disease.

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Pathway-specific deregulation of striatal excitatory synapses in LRRK2 mutations

Cited by 2 publications

References 58 publications

Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

LRRK2 at Striatal Synapses: Cell-Type Specificity and Mechanistic Insights

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