Human LRRK2 G2019S mutation represses post-synaptic protein PSD95 and causes cognitive impairment in transgenic mice

Abstract

Background-LRRK2 G2019S mutation is associated with increased kinase activity and is the most common mutation associated with late-onset PD. However, the transgenic mouse model has not recapitulated cardinal PD-related motor phenotypes. Non-motor symptoms of PD including cognitive impairments are very common and may appear earlier than the motor symptoms. The objective of this study was to determine whether human LRRK2 with G2019S mutation causes hippocampus-dependent cognitive deficits in mice.Results-Male (LRRK2-G2019S) LRRK2-Tg mice showed impairments in the early portion of the Two-day radial arm water maze acquisition trial as well as in the reversal learning on the third day. However, their performance was similar to Non-Tg controls in the probe trial. LRRK2-Tg mice also displayed impairments in the novel arm discrimination test but not in the spontaneous alternation test in Y-maze. Interestingly, there was no statistically significant locomotor impairment during any of these cognitive test, nor in the locomotor tests including open field, accelerating rotarod and pole tests. Expression of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin was lower in hippocampal homogenates of LRRK2-Tg mice.Conclusion-Consistent with previous reports in human LRRK2 G2019S carriers, the current data suggests that cognitive dysfunctions are present in LRRK2-Tg mice even in the absence of locomotor impairment. LRRK2 G2019S mutation represses the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. This study also suggests that mild cognitive impairment may appear earlier than motor dysfunctions in LRRK2-G2019S mutation carriers.

High-fat diet worsens the impact of aging on microglial function and morphology in a region-specific manner

“…Several groups have seen changes in only one of a pre-or a post-synaptic marker (e.g. (Adeosun et al, 2017;Jiang et al, 2015)), and Wang and Mitchell note that eight-carbon medium chain triglycerides in the diet elevate synaptophysin in the hippocampus and improve novel object recognition without affecting PSD-95 (Wang & Mitchell, 2016). Enlarged areas of synaptophysin labelling are associated with dystrophic neurites and have been seen juxtaposed with amyloid plaques (Takeuchi et al, 2000).…”

PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2

“…According to this model, ROC may represent the signaling output of LRRK2 and modulation of 14-3-3γ binding may be implicated in controlling LRRK2 cellular cascades. One of best characterized phenotype caused by mutant LRRK2 in neurons is a reduction of neurite complexity (MacLeod et al, 2006 ; Sepulveda et al, 2013 ; Matikainen-Ankney et al, 2016 ), which may represent an early event before neuronal degeneration and motor dysfunction observed in some PD-LRRK2 models (Li et al, 2010 ; Melrose et al, 2010 ; Winner et al, 2011 ; Longo et al, 2014 ; Beccano-Kelly et al, 2015 ; Yue et al, 2015 ; Adeosun et al, 2017 ). Here we used the BAC-mLRRK2G2019S mouse (Li et al, 2010 ), which was previously shown to display the neurite shortening phenotype (Sepulveda et al, 2013 ) and to show signs of neurodegeneration in the substantia nigra pars compacta at 18 months of age (Chen et al, 2017 ), to investigate the potential implication of our findings in LRRK2-PD.…”

A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2

“…The R1441C/G mutation disrupts the interaction between LRRK2 and PKA, causing aberrant phosphorylation of downstream proteins (Muda et al, 2014 ; Parisiadou et al, 2014 ). Lastly, a recent report found a reduction in the scaffolding protein PSD-95 within the hippocampus of hG2019S-LRRK2 transgenic mice, arguably contributing to an observed cognitive impairment (Adeosun et al, 2017 ). That said, PSD-95 levels were not altered in cultured cortical neurons (Beccano-Kelly et al, 2014 ) or striatal slices (Matikainen-Ankney et al, 2016 ) from GKI mice; thus, further investigation is required to determine whether discrepancies are due to age, neuronal type, and/or LRRK2 expression levels.…”

“…In contrast, others found exaggerated responses to D2 agonism in older G2019S knock-in mice (Tozzi et al, 2018 ). Such changes to long- and short-term plasticity at excitatory synapses may underlie some cognitive and psychiatric phenotypes observed in LRRK2 mouse models (Volta et al, 2015a ; Adeosun et al, 2017 ; Matikainen-Ankney et al, 2018 ; Guevara et al, 2020 ).…”