ASO-mediated knockdown or kinase inhibition of G2019S-Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages

Genetic variation around the LRRK2 gene affects risk for both familial and sporadic Parkinson’s disease (PD). LRRK2 levels have become an appealing target for potential PD therapeutics with LRRK2 antisense oligonucleotides (ASOs) now moving toward clinical trials. However, LRRK2 has been suggested to play a fundamental role in peripheral immunity, and it is currently unknown if targeting increased LRRK2 levels in peripheral immune cells will be beneficial or deleterious. Here it was observed that G2019S macrophages exhibited increased stimulation-dependent lysosomal tubule formation (LTF) and MHC-II trafficking from the perinuclear lysosome to the plasma membrane in an mTOR-dependent manner with concomitant increases in pro-inflammatory cytokine release. Both ASO-mediated knockdown of mutant Lrrk2 and LRRK2 kinase inhibition ameliorated this phenotype and decreased these immune responses in control cells. Given the critical role of antigen presentation, lysosomal function, and cytokine release in macrophages, it is likely LRRK2-targeting therapies with systemic activity may have therapeutic value with regard to mutant LRRK2, but deleterious effects on the peripheral immune system, such as altered pathogen control in these cells, should be considered when reducing levels of non-mutant LRRK2.