α-Synuclein is part of a diverse and highly conserved interaction network that includes PARK9 and manganese toxicity

Abstract

Parkinson's disease (PD), dementia with Lewy bodies, and multiple system atrophy, collectively referred to as synucleinopathies, are associated with a diverse group of genetic and environmental susceptibilities. The best studied of these is PD. α-Synuclein (α-syn) plays a key role in the pathogenesis of both familial and sporadic PD, but evidence linking it to other predisposition factors is limited. Here we report a strong genetic interaction between α-syn and the yeast orthologue of the PD-linked gene PARK9 (ATP13A2). Dopaminergic neuron loss caused by α-syn overexpression in animal and neuronal PD models is rescued by co-expression of PARK9. Further, knockdown of the PARK9 orthologue in C. elegans enhances α-syn misfolding. These data provide a direct functional connection between α-syn and another PD susceptibility locus. Manganese exposure is an environmental risk factor linked to PD and PD-like syndromes. Remarkably, we discovered that yeast PARK9 helps to protect cells from manganese toxicity. Our studies reveal a striking connection between PD genetics (α-syn and PARK9) and an environmental risk factor (PARK9 and manganese). Finally, we show that additional genes from our yeast screen, with diverse functions, are potent modifiers of α-syn-induced neuron loss in animals, establishing a diverse, highly conserved interaction network for α-syn.

A Predictable Worm: Application of Caenorhabditis elegans for Mechanistic Investigation of Movement Disorders

“…(b) Yeast screens for suppressors of α-synuclein toxicity have yielded gene candidates that were subsequently examined in C. elegans and drosophila for the ability to reduce the neurodegeneration associated with α-synuclein overexpression. Candidates that reduce toxicity in both yeast and invertebrate neuronal systems also protected rat primary neurons from degeneration following transfection with A53T α-synuclein [24,28]. (c) A C. elegans hypothesis-based RNA interference (RNAi) screen for effectors of α-synuclein protein misfolding [14] identified candidates that were reported to cause neurodegeneration in a mouse knockout model (ATG7 [37]), as a risk factor for PD (ULK2 [36]), or neuroprotective in human cells when overexpressed (VPS41 [33]).…”

“…We have shown that expression of the worm YPK9 ortholog, W08D2.5 (catp-6), suppressed α-syn-induced DA neurodegeneration in the worm. The human YPK9 ortholog (ATP13A2) has been shown to suppress α-syn-induced cell death in rat primary neuronal culture [28] (Fig. 3b).…”

Amyloid formation and disaggregation of α-synuclein and its tandem repeat (α-TR)

“…a-Synuclein, which is involved in neuronal plasticity, stabilization of lipid membranes, neurotransmitter release, and protein networks, is the major building block of the pathological fibrillar deposits within Lewy bodies [1][2][3]. a-Synuclein is a small (14 kDa) low-structured protein, possessing several imperfect KTKEGV repeats in the N-terminal portion (a.a. 1-95), and an highly acidic C-terminal portion (a.a. 96-140).…”

“…As a first step, we have investigated the interaction of asynuclein with ionic liquids, using several biochemical techniques, including Thioflavin T assays and transmission electron microscopy (TEM). We showed a rapid formation of a-synuclein amyloid fibrils stimulated by 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [BIMbF 3 Im]. Furthermore, the effect of [BIMbF 3 Im] on the a-synuclein tandem repeat (a-TR) in the aggregation process was studied.…”

“…We showed a rapid formation of a-synuclein amyloid fibrils stimulated by 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [BIMbF 3 Im]. Furthermore, the effect of [BIMbF 3 Im] on the a-synuclein tandem repeat (a-TR) in the aggregation process was studied. Our data shows that these fibrils could be disaggregated by the polyphenols such as epigallocatechin gallate (EGCG) and baicalein.…”