. Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. J Neurosci. 2014 Jan 8;34(2):418-33. PubMed.


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  1. In this paper, Skibinski et al. use cellular models to assess LRRK2 toxicity. They use automated imaging to assess the time of death of large cohorts of cells and come to the interesting observation that “soluble” LRRK2 levels positively correlate with earlier cell death. Neither kinase activity nor the presence of inclusion bodies contribute to this phenotype. How increased LRRK2 results in cell death remains to be elucidated, but the results now make it clear that non-kinase-dependent effects of soluble LRRK2 are relevant for cellular physiology. The results also place in proper context the fact that numerous pathogenic mutations in LRRK2 exist that do not result in increased (or decreased) kinase activity. The existence of such mutations is indeed consistent with the hypothesis that altered kinase activity per se is not the sole driving force that causes Parkinson’s disease.

    Is the LRRK2 kinase activity then irrelevant? Previous work has implicated LRRK2 kinase function in important neuronal and cellular processes, including synaptic transmission and vesicle trafficking.  Furthermore, this domain is conserved over several million years of evolution, suggesting it harbors functional relevance. However, whether these actions of the kinase domain are relevant to the disease is indeed unclear.  Similarly, additional work will be needed to determine to what extent the phenotype assessed in the work by Skibinski et al., “time of cell death in vitro,” is relevant to Parkinson’s disease in vivo. Nonetheless, the current work aids in shifting focus toward addressing the non-kinase-dependent effects of LRRK2, and this is an important contribution.

  2. The exciting findings presented here by Skibinski et al. provide key insights into the cellular role of LRRK2 in neurodegeneration underlying Parkinson’s disease (PD). The authors used a longitudinal, real-time imaging platform to individually track primary rodent neurons ectopically expressing tagged mutant or wild-type LRRK2, as well as tracking LRRK2 patient-derived human neurons. They elegantly demonstrated that toxicity of ectopically expressed LRRK2 depended on the levels of diffuse LRRK2 and α-synuclein, but not LRRK2 kinase activity, per se. Pharmacological or genetic inhibition of LRRK2’s kinase function lowered the protein’s levels, thereby causing less neurodegeneration.

    These findings are very appealing as they could explain why pathogenic mutations are found in functional domains other than the kinase domain of LRRK2. They could potentially all lead to the generation of diffuse toxic LRRK2 entities. Together with the synergistic or independent/indirect event of α-synuclein build-up, and interference with cellular homeostasis during aging, this could indeed shed some light on the pathophysiological mechanisms of PD.

    In subsequent studies, it would be important to determine whether endogenously expressed LRRK2 with pathogenic mutations (e.g., in LRRK2 G2019S patient-derived neurons) produces more diffuse toxic LRRK2 protein in comparison to LRRK2 wild-type, or if such diffuse toxic LRRK2 protein is only found when ectopically overexpressed. If the former turns out to be true, therapeutics that help promote more efficient sequestration of toxic diffuse LRRK2 may be a viable therapeutic strategy against LRRK2-mediated toxicity, as the authors suggest. Though difficult to achieve, this would leave normal LRRK2 unaffected, which would be highly desirable as the findings from LRRK2 knockout studies in rodents demonstrated an important role for LRRK2 in kidney and lung function.

    Of note, it remains puzzling why overexpression of G2019S-mutated human LRRK2 in non-dopaminergic mouse neurons in vivo resulted in diffuse LRRK2 staining in the brainstem and cortical neurons, but did not lead to overt degeneration of these neurons or to accelerated α-synuclein-driven neurodegeneration in the brainstem (see Herzig et al., 2012).

    The LRRK2 field has suffered from a lack of validation experiments. We would embrace efforts to strengthen the interesting hypothesis of Skibinski  and co-workers with experiments from different labs that confirm these new insights. We rely on solid, reproducible data to establish preclinical models to develop promising medication for those in need.

  3. This is an intriguing study. LRRK2 belongs to a class of enzymes termed “protein kinases.” LRRK2 is frequently mutated in Parkinson’s. Between 1-2 percent of Parkinson’s cases may be caused by mutations in the gene that encodes for the LRRK2 enzyme. To my knowledge, the evidence that LRRK2 is implicated in Alzheimer’s is weak. The assumption has always been that the protein kinase enzymatic function of LRRK2 was the critical entity for understanding how it operates and how it is linked to Parkinson’s disease.

    Indeed, there is some evidence to support this. For example, the most frequent LRRK2 mutation (G2019S) lies within the heart of the kinase domain and this mutation significantly increases kinase catalytic activity. However, in contrast, this study by Skibinski et al. provides some evidence that the kinase activity of LRRK2 may be less critical than assumed by most researchers. The authors show, in a cell culture overexpression toxicity model, that LRRK2 toxicity is independent of its kinase activity. Instead, their data reveal that the absolute levels of LRRK2 expressed in cells is the most important factor. The data also suggest that expression of another protein, α-synuclein, which is strongly linked to Parkinson’s as well as Alzheimer’s, is also a critical determinant for LRRK2-mediated toxicity. 

    I feel that this paper makes a useful contribution to the literature as it highlights the importance of studying absolute LRRK2 protein levels, and studying whether variation of these levels is a key factor in Parkinson’s. It is possible that some of the LRRK2 Parkinson’s mutations could influence the expression levels of the kinase and this could be the mechanism by which they drive toxicity. LRRK2 also contains a GTPase catalytic domain, a leucine-rich repeat, and a highly conserved C-terminal tail, which are all likely to play critical roles. The importance of some of these other domains has been previously overlooked while everyone has focused on finding substrates for LRRK2. The Skibinski study suggests that more analysis of the other domains of LRRK2 is warranted, and that we should also be studying the importance of absolute LRRK2 expression as a factor mediating LRRK2 toxicity.

    I am not an expert in the analysis of neuronal toxicity, but I notice that many of the studies in the Skibinski paper are undertaken by overexpressing wild-type and mutant forms of LRRK2 in primary neuronal cells. Previous work has shown that there is always the danger in overexpression studies that this approach could lead to the observed phenotype through a non-physiological perturbation of the cell system. Nevertheless this is an interesting paper that will stimulate further research into LRRK2. It will also be interesting to learn more about the molecular mechanism by which LRRK2 interacts with α-synuclein, and whether this has a role to play in Alzheimer's.

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This paper appears in the following:


  1. Rethinking LRRK2 Toxicity: It’s How Much Is Present, Not What It Does