OBJECTIVE The presence in the brain of α-synuclein containing Lewy neurites, or bodies, is the histological hallmark of Parkinson's disease (PD). The discovery of α-synuclein aggregates in nerve endings of the heart, digestive tract, and skin has lent support to the concept of PD as a systemic disease. Our goals were, first, to demonstrate the presence of α-synuclein inclusions in the skin and,...

The misfolding of α-synuclein is a critical event in the death of dopaminergic neurons and the progression of Parkinson's disease. Previously, it was suggested that drugs, which bind to α-synuclein and form a loop structure between the N- and C-termini, tend to be neuroprotective, whereas others, which cause a more compact structure, tend to be neurotoxic. To improve the binding to α-synuclein,...

There is striking evidence that heat shock protein 70 (Hsp70) negatively regulates α-synuclein aggregation, which plays a significant role in the formation and progression of Parkinson disease (PD). However, how the Hsp70 in neurons fails to prevent or even reverse α-synuclein aggregation and toxicity in PD still remains to be determined. In the present study, we constructed an α-synuclein-over...

The native function of α-synuclein is thought to involve regulation of synaptic vesicle trafficking. Recent work has also implicated a role in neurotransmission, possibly through interactions with the proteins involved in synaptic vesicle fusion. Here, we demonstrate that α-synuclein inhibits SNARE-mediated vesicle fusion through binding the membrane, without a direct interaction between α-synu...

Previously, we have showed that overexpression of methionine-oxidized α-synuclein in methionine sulfoxide reductase A (MsrA) null mutant yeast cells inhibits α-synuclein phosphorylation and increases protein fibrillation. The current studies show that ablation of mouse MsrA gene caused enhanced methionine oxidation of α-synuclein while reducing its own phophorylation levels, especially in the h...

Parkinson's disease (PD), a progressive neurodegenerative disorder, is characterized by irreversible dopaminergic neuron loss and intra-neuronal α-synuclein aggregation. High mobility group box 1 (HMGB1) has been proven to be involved in autophagy dysfunction induced by α-synuclein accumulation, and the Beclin1-vacuolar protein sorting 34 (Vps34) complex is of great importance to the initiation...

KLK6 is a serine protease highly expressed in the nervous system. In synucleinopathies, including Parkinson disease, the levels of KLK6 inversely correlate with α-synuclein in CSF. Recently, we suggested that recombinant KLK6 mediates the degradation of extracellular α-synuclein directly and via a proteolytic cascade that involves unidentified metalloproteinase(s). Here, we show that recombinan...

There is mounting evidence for a role of mitochondrial dysfunction in the pathogenesis of α -synucleinopathies such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In particular, recent studies have demonstrated that failure of mitochondrial quality control caused by loss of function of the PTEN-induced kinase 1 (PINK1, PARK6) Parkin (PARK2) pathway may be causative in some fam...

Interactions of oligomeric aggregates of the intrinsically disordered protein α-synuclein with lipid membranes appear to play an important role in the development of Parkinson's disease. The permeabilization of cellular membranes by oligomers has been proposed to result in neuronal death. The detailed mechanisms by which α-synuclein oligomers permeabilize lipid bilayers remain unknown. Two diff...

Aggregation of α-synuclein has been linked to both familial and sporadic Parkinson's disease. Recent studies suggest that α-synuclein aggregates may spread from cell to cell and raise questions about the propagation of neurodegeneration. While continuous progress has been made characterizing α-synuclein aggregates in vitro, there is a lack of information regarding the structure of these species...