Drug Discovery Opinion

Although mutations in the gene for leucine-rich repeat kinase 2 (LRRK2) have been linked to both familial and sporadic cases of Parkinson’s disease, the exact cellular function of LRRK2 remains unclear. The mechanisms by which mutated LRRK2 variants contribute to Parkinson’s disease are also unclear but it is believed that they lead, directly or indirectly, to increased kinase activity and promote inclusion formation leading to neurotoxicity. Researchers at the University of Texas Southwestern Medical Center have now identified a strong interaction between LRRK2 and CHIP (C-terminus of Hsp70-Interacting Protein), an E3 ubiquitin ligase which is crucial for the ubiquitination of several heat shock protein (Hsp70/Hsp90) client proteins involved in neurodegenerative disease. The screen also confirmed a robust interaction between LRRK2 and Hsp90, which had previously been identified as a LRRK2 binding protein. CHIP was further found to be able to significantly reduce cellular levels of LLRK2 in a dose-dependent fashion, most likely by ubiquitination and subsequent proteasome-dependent degradation. CHIP-mediated degradation of both wild type and mutant LRRK2 was found to be similar.

CHIP was found to be able to bind to LRRK2 in at least two different ways: directly or indirectly, but independent of Hsp90, to the ROC (Ras of complex) domain of LRRK2 via CHIP’s charged domain; indirectly, via Hsp90, to the N-terminal domain of LRRK2 via the TPR (tetratricopeptide repeat) domain of CHIP. Hsp90 was shown to block CHIP-mediated degradation of LRRK2, which could be overcome using the Hsp90 inhibitor, geldanamycin.

The authors hope that the discovery of cellular mechanisms that regulate LRRK2 will provide new therapeutic targets for the treatment of familial and sporadic Parkinson’s disease.

The study is published in the journal PloS ONE.

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