Environmental neurotoxic challenge of conditional alpha-synuclein transgenic mice predicts a dopaminergic olfactory-striatal interplay in early PD

Abstract

The olfactory bulb (OB) is one of the first brain regions in Parkinson’s disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD.

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…None of these effects occurs in PQ-treated mice with suppressed a-syn expression. Loss of DA neurons in the olfactory bulb is evident in PQ-treated mutant mice but not in both PQ-treated mice with suppressed a-syn expression (after doxycycline administration) and untreated mutant mice (Nuber et al, 2014) In vitro system overexpressing the neuroprotective molecular chaperone human DJ-1, showed more resistance to the proteasome impairment induced by paraquat. Similarly, preservation was observed in the same system following treatment with a known proteasome inhibitors (epoxomycin) However, although evidence exists to support some essentiality of impaired proteostasis, a single molecular chain of events cannot be established…”

Caspase-1 clipping causes complications for α-synuclein

“…This protease is known to cleave αSyn at residue 122 into a C-terminally truncated, aggregation-prone form, similar to that seen in affected regions of PD and DLB brain (8,10,12). There is a dual adverse effect of activating calpain-1: it cleaves αSyn and thus induces neurotoxicity on the one hand, and it inhibits autophagy and thereby full proteolytic degradation of αSyn on the other (8). In a related work, coexpression of the natural calpain inhibitor, calpastatin, decreased αSyn truncation and aggregation in vivo (20).…”

“…The increased brain levels of these fragments observed in PD and dementia with Lewy bodies (DLB) (7,8) and the vulnerability of dopaminergic neurons in αSyn transgenic (tg) rodents to enhanced C-terminal truncation [e.g., due to overexpression (9) or PD-relevant toxins (8)] all argue for a critical threshold of truncated αSyn. Notably, such truncated species can accelerate the aggregation of the full-length αSyn protein in vitro (10) and in vivo (11), and thus may contribute to or even initiate the aggregation process.…”

“…A common finding in both familial PD αSyn tg mice and wild-type animals exposed to either PD-linked pesticides or inflammogens is an increase in neuronal levels of αSyn and/or its shift to insoluble, aggregated forms (8,15,16). Previous work by one of us identified a significant increase in C-terminally truncated αSyn in mice exposed to low doses of paraquat or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (8,17). Paraquat exposure typically results in activation of calpain (18) (Fig.…”

“…1), a calcium-dependent protease implicated in PD (19). This protease is known to cleave αSyn at residue 122 into a C-terminally truncated, aggregation-prone form, similar to that seen in affected regions of PD and DLB brain (8,10,12). There is a dual adverse effect of activating calpain-1: it cleaves αSyn and thus induces neurotoxicity on the one hand, and it inhibits autophagy and thereby full proteolytic degradation of αSyn on the other (8).…”