The impact of murine LRRK2 G2019S transgene overexpression on acute responses to inflammatory challenge

Leucine Rich Repeat Kinase 2 and Innate Immunity

“…A similar result of potentiated inflammatory cytokines was obtained with LPS treated primary cells from R1441G transgenic mice (Gillardon et al, 2012). However, potentiated cytokine profiles were not observed in studies employing LPS treated G2019S transgenic mice (Moehle et al, 2015;Litteljohn et al, 2018), or G2019S mouse macrophages infected with S. typhimurium (Shutinoski et al, 2019). Thus, it seems that context is important for LRRK2 immunological responses and perhaps unsurprisingly, responses may differ between mutations, species and nature of the stimuli.…”

Environmental toxicant exposure and Parkinson’s disease: LRRK2 and inflammatory processes

“…Our experiments in chapter 4 found no evidence of altered inflammation in G2019S overexpressing mice, however, we did observe a series of stressor-related effects. These findings line-up with reports that these mice and their bacterially transfected G2019S overexpressing counterparts do not show inflammatory alterations [368]. Interestingly, our stressor linked findings were replicated in another overexpressing model [339], suggesting that overexpression of LRRK2 may play a role in some of the co-morbid features of PD, such as depression and anxiety.…”

“…The stress phenotype of the G2019S mice is intriguing in that it raises the possibility that the mutation could specifically favor the development of psychiatric disturbances, which are commonly co-morbid with PD [368][369][370]. Indeed, the basal elevation of 5-HT1A we observed in G2019S mutants is consistent with a recent report that also found these mice to display anxiety and depressive-like behaviors [339].…”

“…Similarly, the basally increased corticosterone we observed in the G2019S mice could conceivably have been modulating behaviors. It is important to note that unlike these 6-8 month old animals, we recently found that 2-month-old G2019S overexpressing mice had no such basal behavioral or corticoid differences [368], suggesting that age is critical for the manifestation of the "stress" phenotype.…”

“…Alternatively, knockout of endogenous LRRK2 clearly blunted the HPA response and this could stem from reduced kinase activity, as well as potential reductions in protein signaling pathways, most notably, p38, JNK, interferon-gamma, as well as a number of RAB proteins that control vesicular trafficking, autophagy and lysosomal functioning [78]. We and others did find that G2019S overexpression markedly altered basal and immune challenge evoked dopaminergic activity within the striatum [366][367][368]. But again, these transgenic mice did not show changes in pathology or inflammatory parameters, including sickness behaviors or circulating cytokines.…”