Plant poisoning leads to alpha-synucleinopathy and neuromelanopathy in kangaroos

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.

A review of phytoconstituents and biological activities of genus Phalaris

“…Abietane diterpenes were isolated from hexane fraction of P. canariensis seeds including canarien A (24), abietatrien-3bacetyl-6,19-olide (34) and abietatrien-3β-acetyl-2bol-6,19olide (35) [22,23] . Furthermore, diterpenes of pimaranes type were reported from hexane fraction of P. canariensis seeds such as canarien B (25) (32), and 19hydroxy-3β,11α-diacetylpimara-15-ene (33) [22,23].…”

“…These alkaloids are primarily indolederived tryptamine alkaloids, particularly N,Ndimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), which have structures similar to serotonin and can cause dysfunction in both cardiac system and central nervous system. [27][28][29][30][31][32][33].…”

Case Report: Synucleinopathy Associated With Phalaris Neurotoxicity in Sheep

“…For this study, histopathology and immunohistochemistry were performed as described (2). Briefly, the brains of sheep were fixed by immersion in 10% neutral buffered formalin.…”

“…Immunofluorescence staining was performed as described (2). Briefly, brain sections were processed for immunohistochemical procedures then stained with GFAP mouse monoclonal antibody IgG (EMD Millipore, MAB360) or 97/8 rabbit polyclonal antibody for 1 h at room temperature.…”

“…A recent study by Tayebi and colleagues demonstrated that Phalaris toxicity (PT) led to an accumulation of neuromelanin and aggregated α-synuclein in the central and peripheral nervous system of kangaroos after intoxication with tryptamine-alkaloid-rich Phalaris spp. pasture plants (2). PT is known to affect sheep as well as cattle and horses at pasture; this widely used and studied perennial pasture plant can become toxic after heavy rainfall, which follows a prolonged period of dry weather (3).…”