G2019S LRRK2 and aging confer susceptibility to proteasome inhibitor-induced neurotoxicity in nigrostriatal dopaminergic system

Abstract

The leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is one of the most common genetic causes in Parkinson's disease (PD). The penetrance of G2019S LRRK2 is incomplete and is age-dependent, therefore, it has been speculated that environmental toxins and aging could contribute to G2019S LRRK2-related PD pathogenesis. To prove this speculation, we performed a longitudinal investigation in mice bearing G2019S LRRK2 mutation. BAC G2019S LRRK2 transgenic (Tg) mice and their wildtype (Wt) littermates were treated with lactacystin, a specific proteasome inhibitor. The susceptibilities of mice to lactacystin-induced nigrostriatal dopaminergic (DAergic) degeneration were evaluated, at 5 and 12 months of age. We found that lactacystin treatment caused a greater decline of striatal DA content in the Tg mice at either 5 or 12 months of age than their age-matched Wt littermates. Moreover, the lactacystin-treated Tg or Wt mice at 12 months of age lose much more nigral tyrosine hydroxylase (TH)-positive neurons than the mice at 5 months of age, indicating an age-associated DAergic neurotoxicity. Additionally, stereotactic injection of lactacystin induced a dramatic increase of activated microglia in substantia nigra of mice at 12 months of age, compared with mice at 5 months of age. In summary, our study suggests that expression of the G2019S mutation in the mouse LRRK2 gene confers an age-associated high susceptibility to proteasome inhibition-induced nigrostriatal DAergic degeneration.

The FOXP2-Driven Network in Developmental Disorders and Neurodegeneration

“…ROCK1 is implicated in neuronal regeneration and neuritogenesis (Da Silva et al, 2003; Tang et al, 2012). Moreover, mutations in LRRK2 gene represent the most frequent genetic cause of late-onset PD (Paisan-Ruiz et al, 2008), possibly due to negative effects on neuritogenesis and survival of nigrostriatal dopaminergic neurons (Han et al, 2008; Xiao et al, 2015). The links between our LCC and neurodegeneration are even more manifest when considering that pERM is required for proteolytic processing of amyloid precursor protein (APP) by α-secretases into the neuroprotective soluble APP ectodomain (sAPPα) (Darmellah et al, 2012).…”

Sex and LRRK2 Genotype Differences in Inflammation and Dopaminergic Neurodegeneration in a Multi-Hit Model of Parkinson's Disease

“…between 12 and 16 months) (Chen et al, 2012). Consistently, in a recent report that looked at the interactive actions of the G2019S mutation and the proteasomal inhibitor, lactacystin, synergistic effects in DAergic cell loss were, similarly, observed in aged mice (Xiao et al, 2015). Thus when considering these previous reports and the absence of a genotype effect in the current study, it appears that age is an indispensible factor required to bring forth the G2019S relevant pathology.…”

“…Indeed, the synergistic effects of the G2019S mutation and proteasomal inhibition on DAergic neuronal loss were reported in aged animals (i.e. 12 months) (Xiao et al, 2015).…”

“…These data raise the possibility that the G2019S mutation may act as a vulnerability factor that could enhance the neurotoxic actions of environmental risk factors. Accordingly, a recent report found that when G2019S transgenic mice were treated with lactacystin, a proteasome inhibitor, they displayed greatly enhanced nigrostriatal dopaminergic degeneration and greater decline in striatal DA content compared to G2019S-alone and wild-type mice (Xiao et al, 2015). Moreover, this effect was more pronounced at 12 months compared to 5 months, indicating increased pathology with the passage of time and/or advancing age (Xiao et al, 2015).…”

“…Such deficits in behaviour are only sparingly observed in WT mice treated with PQ or in aged DJ-1 mutated mice (Yang et al 2007). Moreover, in a recent report, it was found that when G2019S transgenic mice were treated with lactacystin, a proteasome inhibitor, they displayed significantly greater nigrostriatal DAergic degeneration and greater decline in striatal DA content compared to G2019S and WT controls (Xiao et al, 2015). Moreover, this effect was more pronounced at 12 months compared to 5 months, indicating that the environmental toxin was sufficient at enhancing the penetrance of G2019S in an age-dependent manner (Xiao et al, 2015).…”