Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease?

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

“…Another mutation, the N1437H mutation that causes PD in a large Norwegian kindred, seems to increase GTP binding, which could suggest an overall reduction in GTPase activity (Table II and Figure 1) (Rudenko et al, 2012). …”

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

“…Furthermore, apart from G2019S none of other LRRK2 mutations consistently augment kinase activity of the protein [78]. Therefore, application of kinase inhibitors in case of these substitutions may or may not be sensible, and alternative therapeutic approaches might be considered in these cases [164,165]. Moreover, some variants, like G2385R, have diminished kinase activity and are still associated with disease [73].…”

“…Along the same lines, our recent results showing enhancement of LRRK2 activity in cells by interactions with Rab7L1 and GAK may suggest additional targets. Dimerization of LRRK2 itself is also thought to contribute to its activity and might be targetable if the structural basis of this phenomenon were elucidated [164].…”

“…Therefore, modulation of up-and downstream effectors of LRRK2 could compensate for the pathogenic effects of mutations [164]. For example, activation of 4E-BP by rapamycin or transgenic overexpression of 4E-BP prevents dopamine neuron loss in Drosophila models [75,166].…”

Parkinson’s Disease: New Insights

“…The evidence of a correlation between PD and mitochondrial dysfunction arises from a number of considerations, including the following: i) mutations in the neuroprotective genes PINK-1 [16][17][18] and LRRK2 [19][20][21] affect mitochondrial homeostasis as well as the biochemical reactions ensuring basic functions such as energy supply, calcium buffering, respiratory activity etc., the impairment of which can drive neurodegeneration; ii) the activity of kinases involved in regulating mitochondrial biology under the influence of ROS (Akt, JNK, ERK, c-JUN, PINK-1) is generally altered in PD patients or PD experimental models, possibly promoting mitochondrial dysfunction [22]; iii) given that the loss-of-function of mitochondria is often associated to deletions of mtDNA, the exogenous introduction of mtDNA restores mitochondria bioenergetics [23].…”