Plant poisoning leads to alpha-synucleinopathy and neuromelanopathy in kangaroos

Mourad Tayebi,Monique David,Colin Masters,Liliana Tatarczuch,Larry Walker,Meena Mikhael,Pam Whiteley,Qiao-Xin Li,Charles M El-Hage,Kirsty Ferguson,Umma Habiba,Brian A Summers,Ian Birchall,Shiji Varghese,Mirjana Bogeski,David Harman,Pedro Pinczowski

doi:10.1038/s41598-019-53396-8

Abstract

The pathogenesis of synucleinopathies, common neuropathological lesions normally associated with some human neurodegenerative disorders such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, remains poorly understood. In animals, ingestion of the tryptamine-alkaloid-rich phalaris pastures plants causes a disorder called Phalaris staggers, a neurological syndrome reported in kangaroos. The aim of the study was to characterise the clinical and neuropathological changes associated with spontaneous cases of Phalaris staggers in kangaroos. Gross, histological, ultrastructural and Immunohistochemical studies were performed to demonstrate neuronal accumulation of neuromelanin and aggregated α-synuclein. ELISA and mass spectrometry were used to detect serum-borne α-synuclein and tryptamine alkaloids respectively. We report that neurons in the central and enteric nervous systems of affected kangaroos display extensive accumulation of neuromelanin in the perikaryon without affecting neuronal morphology. Ultrastructural studies confirmed the typical structure of neuromelanin. While we demonstrated strong staining of α-synuclein, restricted to neurons, intracytoplasmic Lewy bodies inclusions were not observed. α-synuclein aggregates levels were shown to be lower in sera of the affected kangaroos compared to unaffected herd mate kangaroos. Finally, mass spectrometry failed to detect the alkaloid toxins in the sera derived from the affected kangaroos. Our preliminary findings warrant further investigation of Phalaris staggers in kangaroos, potentially a valuable large animal model for environmentally-acquired toxic synucleinopathy.

Highlights

The pathogenesis of synucleinopathies, common neuropathological lesions normally associated with some human neurodegenerative disorders such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, remains poorly understood
The molecular mechanisms underlying the accumulation of intracytoplasmic α-synuclein inclusions in human neurodegenerative disorders, including idiopathic Parkinson’s disease (PD), PD dementia, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA)[1] remains elusive
The demonstration that the nigrostriatal-toxic addictive ‘street designer drug’ N-methyl- 4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), structurally analogous to tryptamine alkaloids (TA)-derivatives produced in vivo[2], leads to long-lasting parkinsonism in humans and monkeys[3,4,5,6], highlighted the possible involvement of alkaloids in Parkinsonism syndromes, including idiopathic Parkinson’s disease[7,8]

Summary

Introduction

The pathogenesis of synucleinopathies, common neuropathological lesions normally associated with some human neurodegenerative disorders such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, remains poorly understood. Ingestion of the tryptamine-alkaloidrich phalaris pastures plants causes a disorder called Phalaris staggers, a neurological syndrome reported in kangaroos. PT has been reported since the 1940’s with a worldwide prevalence[12,17,20,21] and occurs in grazing animals characteristically during a prolonged period of dry weather that precedes rainfall[22] Because these are widely cultivated perennial pasture plants, over many decades phalaris toxicity in livestock has been important in Australia, New Zealand, South Africa, USA and Norway[23]. The clinical presentation resembled that seen in sheep and included the typical Phalaris-associated neurological signs such as ataxia, hyper-excitability, muscle tremors, abnormal gait, paresis, convulsions, recumbency and death[22]. The neuropathological changes described in these kangaroos were reported to be similar to those described in sheep affected with Phalaris staggers and included pronounced green discoloration of the grey matter, that appeared microscopically as intraneuronal brown pigmentation[22]

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