LRRK2 Signalling Pathways in Parkinson’s Disease

Abstract

This work is licensed under Creative Commons Attribution 4.0 License ANN.MS.ID.000540.

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“…LRRK2 is widely expressed in human tissues. Loss of LRRK2 has been shown to have a pathological phenotype in kidney and lung tissues [41], pharmacological LRRK2 kinase inhibition induces LRRK2 protein destabilization and proteasomal degradation [42], suggesting that normal LRRK2 kinase activity is needed for normal physiological function and LRRK2 kinase inhibitors may have severe adverse effects on normal tissues. However, it would be novel if a LRRK2 kinase inhibitor could be developed for specifically targeting LRRK2 active form [G2019S] without affecting the LRRK2 wild-type kinase.…”

“…However, it would be novel if a LRRK2 kinase inhibitor could be developed for specifically targeting LRRK2 active form [G2019S] without affecting the LRRK2 wild-type kinase. Indeed, clinical success of inhibition of kinases harboring disease causing driver mutations has been quite dramatic in the field of oncology: BRAF(V600E) in melanoma [42], mutant EGFR [43] and EML4-ALK in lung cancer [44], and BCR-ABL in chronic myelogenous leukemia [45]. Therefore it would be possible to pharmacologically interrogate the effects of inhibition of LRRK2[G2019S] in PD to develop appropriate tool compounds using structure based design and evaluate them in available PD disease models.…”