%0 Journal Article
%T Familial Parkinson's Disease Mutant E46K 汐-Synuclein Localizes to Membranous Structures, Forms Aggregates, and Induces Toxicity in Yeast Models
%A Michael Fiske
%A Michael White
%A Stephanie Valtierra
%A Sara Herrera
%A Keith Solvang
%A Alina Konnikova
%A Shubhik DebBurman
%J ISRN Neurology
%D 2011
%R 10.5402/2011/521847
%X In Parkinson＊s disease (PD), midbrain dopaminergic neuronal death is linked to the accumulation of aggregated 汐-synuclein. The familial PD mutant form of 汐-synuclein, E46K, has not been thoroughly evaluated yet in an organismal model system. Here, we report that E46K resembled wild-type (WT) 汐-synuclein in Saccharomyces cerevisiae in that it predominantly localized to the plasma membrane, and it did not induce significant toxicity or accumulation. In contrast, in Schizosaccharomyces pombe, E46K did not associate with the plasma membrane. Instead, in one strain, it extensively aggregated in the cytoplasm and was as toxic as WT. Remarkably, in another strain, E46K extensively associated with the endomembrane system and was more toxic than WT. Our studies recapitulate and extend aggregation and phospholipid membrane association properties of E46K previously observed in vitro and cell culture. Furthermore, it supports the notion that E46K generates toxicity partly due to increased association with endomembrane systems within cells. 1. Introduction Parkinson＊s disease (PD) is a fatal and incurable neurodegenerative disorder characterized by resting tremors, postural instability, and bradykinesia [1]. The death of midbrain substantia nigra neurons characterizes the pathology of both familial and sporadic forms of PD. Two types of molecules accumulate within these dying cells: misfolded and aggregated 汐-synuclein in cytoplasmic inclusions called Lewy bodies [2] and oxidative free radicals [1, 3]. Therefore, a major hypothesis is that 汐-synuclein misfolding and aggregation is linked to neuronal toxicity in PD [4每6]. While the molecular basis of sporadic PD is still unclear, mutations in six genes cause familial PD [7], including three point mutations (A53T, A30P, and E46K) within the 汐-synuclein gene [8每10]. In addition to self-aggregation [11每13], several other 汐-synuclein properties that may be relevant to PD include maintenance of neurotransmitter vesicular pools [14, 15], synaptic plasticity [16, 17], phospholipid binding and lipid metabolism [18每21], microtubule binding [22], chaperone-like ability [23每25], and ER-Golgi trafficking [26, 27]. While the A30P and A53T familial mutants are widely studied in how they alter the above properties to cause cytotoxicity and contribute to PD pathogenesis [28], less is known about the third and most recently discovered familial mutant, E46K. Thus far, E46K is known to aggregate into fibrils more rapidly than wild-type 汐-synuclein in vitro [29, 30] and in cell culture [31]. Additionally, recent biochemical studies
%U http://www.hindawi.com/journals/isrn.neurology/2011/521847/