Physiologically relevant factors influence tau phosphorylation by leucine‐rich repeat kinase 2

Abstract

Hyper-phosphorylation and aggregation of tau are observed in multiple neurodegenerative diseases, termed tauopathies. Tau has also been implicated in the pathogenesis of Parkinson’s disease (PD) and parkinsonisms. Interestingly, a subset of PD patients with mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene exhibit tau pathology. Mutations in LRRK2 are a major risk factor for PD, but LRRK2 protein function remains unclear. The most common mutation, G2019S, is located in the kinase domain of LRRK2 and enhances kinase activity in vitro. This suggests that the kinase activity of LRRK2 may underlie its cellular toxicity. Recently, in vitro studies suggested a direct interaction between tubulin-bound tau and LRRK2 that results in tau phosphorylation at one identified site. Here we present data suggesting that microtubules enhance LRRK2-mediated tau phosphorylation at 3 different epitopes. We also explored the effect of divalent cations as catalytic cofactors for G2019S LRRK2-mediated tau phosphorylation and found that manganese does not support kinase activity and inhibits the efficient ability of magnesium to catalyze LRRK2-mediated phosphorylation of tau. These results suggest that cofactors such as microtubules and cations in the cellular milieu may have an important impact on LRRK2-tau interactions and resultant tau phosphorylation.

What Have We Learned from Cerebrospinal Fluid Studies about Biomarkers for Detecting LRRK2 Parkinson’s Disease Patients and Healthy Subjects with Parkinson’s-Associated LRRK2 Mutations?

“…Phosphorylation is thought to increase tau's neurotoxicity [70] but the influence of phosphorylation on ␣-synuclein's toxicity is unclear [71]. Although some studies have suggested that LRRK2 may phosphorylate ␣synuclein [72] and/or tau [73][74][75], the only presently accepted bona fide LRRK2 kinase substrates are LRRK2 protein itself and some Rab GTPases [76,77] such as Rab10, as mentioned above.…”

Physiological and pathological functions of LRRK2: implications from substrate proteins

“…As mentioned above, a number of reports have described that LRRK2 promotes tau phosphorylation in the brain in BAC-based transgenic mice as well as in knock-in mice of FPD mutant forms of LRRK2. Whereas the direct phosphorylation of tau by recombinant LRRK2 in an in vitro assay has been observed [166], some reports suggested that LRRK2 phosphorylates tau in the presence of tubulin or microtubules [167,168]. Other reports proposed that LRRK2 directly interacts with GSK-3β via the LRRK2 kinase domain, and this interaction enhances the kinase activity of GSK-3β [169].…”

Mitophagy in neurodegenerative diseases

“…The elongation, cargo recognition and completion steps could be affected by alterations in the levels of the clathrin adaptor protein PICALM, as reported in AD (Moreau et al, 2014); hyperphosphorylated Tau-dependent microtubules destabilisation, as in AD and PD (Hamm et al, 2015); defective cargo recognition/interaction, as reported for mHtt in HD, or TDP-43, SOD1 and FUS, in ALS (Menzies et al, 2017).…”