Alpha-synuclein (Syn) plays a central role in the pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recent multicenter genetic studies have revealed that mutations in the glucocerebrosidase 1 (GBA1) gene, which are responsible for Gaucher's disease, are strong risk factors for PD and DLB. However, the mechanistic link between the functional loss of glucocerebrosidase (GCase) and the toxicity of Syn in vivo is not fully understood. In this study, we employed

more »

... la models to examine the effect of GCase deficiency on the neurotoxicity of Syn and its molecular mechanism. Behavioral and histological analyses showed that knockdown of the Drosophila homologue of GBA1 (dGBA1) exacerbates the locomotor dysfunction, loss of dopaminergic neurons, and retinal degeneration of Syn-expressing flies. This phenotypic aggravation was associated with the accumulation of proteinase K (PK)-resistant Syn, rather than with changes in the total amount of Syn, raising the possibility that glucosylceramide (GlcCer), a substrate of GCase, accelerates the misfolding of Syn. Indeed, in vitro experiments revealed that GlcCer directly promotes the conversion of recombinant Syn into the PK-resistant form, representing a toxic conformational change. Similarly to dGBA1 knockdown, knockdown of the Drosophila homologue of β-galactosidase (β-Gal) also aggravated locomotor dysfunction of the Syn flies, and its substrate GM1 ganglioside accelerated the formation of PK-resistant Syn. Our findings suggest that the functional loss of GCase or β-Gal promotes the toxic conversion of Syn via aberrant interactions between Syn and their substrate glycolipids, leading to the aggravation of Syn-mediated neurodegeneration. by guest on November 7, 2016 http://hmg.oxfordjournals.org/ Downloaded from Introduction Parkinson's disease (PD) is one of the most common neurodegenerative diseases, characterized by motor dysfunction, such as resting tremor, bradykinesia, and rigidity. Dopamine (DA) replacement therapy is widely used to improve these motor symptoms, but does not attenuate disease progression. Pathological features of PD include a loss of dopaminergic neurons and the deposition of Lewy bodies (LBs), which are mainly composed of -synuclein (Syn), in the substantia nigra. LBs are also abundantly found in the brains of patients with dementia with Lewy bodies (DLB), suggesting a pathological overlap between PD and DLB (1). Missense mutations in the SNCA gene encoding Syn, as well as genomic multiplications in the region containing the SNCA gene, have been identified as causes of dominantly inherited PD (2). Moreover, genome-wide association studies identified sequence variations in the SNCA gene as major risk factors for sporadic PD (3, 4), suggesting that Syn plays a central role in the pathogenesis of both familial and sporadic cases of PD. Missense mutations in Syn, such as A30P, A53T, and E46K, have been shown to modulate Syn fibril formation, implicating that the misfolding and subsequent aggregation of Syn play key roles in its acquisition of neurotoxicity (5). However, in sporadic PD and DLB, normally harmless Syn proteins without any mutations might gain toxic functions by unknown mechanisms. Thus, it is important to elucidate the factors promoting the toxic conversion of Syn, towards understanding the pathogenesis of and developing disease-modifying therapies for PD and DLB. Recently, multicenter genetic studies revealed that mutations in the glucocerebrosidase 1 (GBA1) gene are strong risk factors for PD (odds ratio: 5.31) (6) and DLB (odds ratio: 8.28) by guest on November 7, 2016 http://hmg.oxfordjournals.org/ Downloaded from