Leucine-rich repeat kinase 2-sensitive Na+/Ca2+ exchanger activity in dendritic cells

Area of Science:

• Immunology
• Cell Biology
• Neuroscience

Background:

• Leucine-rich repeat kinase 2 (LRRK2) gene variants are linked to Parkinson's disease (PD) susceptibility.
• LRRK2 is expressed in immune cells, including dendritic cells (DCs), but its immune function is not fully understood.
• Dendritic cells are crucial antigen-presenting cells bridging innate and adaptive immunity.

Purpose of the Study:

• To investigate the role of LRRK2 in regulating calcium (Ca2+) signaling in dendritic cells.
• To determine the impact of LRRK2 deficiency on Ca2+ handling and Na+/Ca2+ exchanger activity in DCs.

Main Methods:

• Analysis of cytosolic Ca2+ levels ([Ca2+]i) using Fura-2 fluorescence in LRRK2-deficient (Lrrk2(-/-)) and wild-type (Lrrk2(+/+)) mouse DCs.
• Measurement of whole-cell currents to assess electrogenic transport and Na+/Ca2+ exchanger activity (NCX, NCKX).
• Assessment of gene expression (NCX1, NCKX1) and Ca2+ signaling after treatment with an LRRK2 inhibitor (GSK2578215A).

Main Results:

• LRRK2-deficient DCs exhibited significantly larger increases in [Ca2+]i during Ca2+ release and store-operated Ca2+ entry (SOCE).
• Na+/Ca2+ exchanger activity, including slope and peak of Ca2+ transients and exchanger-induced currents, was significantly reduced in Lrrk2(-/-) DCs.
• LRRK2 inhibition decreased NCX1 and NCKX1 transcript levels, blunted Na+/Ca2+ exchanger activity, and augmented Ca2+ signals in DCs.

Conclusions:

• LRRK2 plays a novel role in up-regulating the transcription and activity of Na+/Ca2+ exchangers in dendritic cells.
• This LRRK2-mediated regulation of Na+/Ca2+ exchangers attenuates Ca2+ signaling in DCs.
• The findings provide new insights into LRRK2's function in the immune system and its potential link to immune cell function in PD.