Abstract
α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of α-synuclein, reducing membrane binding, impaired the clearance of α-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of α-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.
Highlights
The molecular underpinnings of neurodegenerative diseases (NDs) such as Parkinson’s disease (PD) and Alzheimer’s disease remain unclear, as genetics explains only a minor fraction of cases
PD is a common disorder known for typical motor symptoms that result from the loss of nigrostriatal dopaminergic neurons (DA), and for the accumulation of pathognomonic intraneuronal inclusions known as Lewy bodies (LBs) and Lewy neurites
MGO induces aSyn aggregation and toxicity in cell models of PD First, we investigated the effect of MGO on aSyn aggregation and toxicity in yeast cells constitutively expressing aSyn (Outeiro and Lindquist, 2003)
Summary
The molecular underpinnings of neurodegenerative diseases (NDs) such as Parkinson’s disease (PD) and Alzheimer’s disease remain unclear, as genetics explains only a minor fraction of cases. PD is a common disorder known for typical motor symptoms that result from the loss of nigrostriatal dopaminergic neurons (DA), and for the accumulation of pathognomonic intraneuronal inclusions known as Lewy bodies (LBs) and Lewy neurites These inclusions are primarily composed of alpha-synuclein (aSyn) (Spillantini et al, 1998; Wales et al, 2013), a protein associated with other disorders known as synucleinopathies. DJ-1 mutations cause autosomal recessive PD through a loss of function mechanism This protein was shown to have both glyoxalase (Lee et al, 2012) and deglycase activities (Richarme et al, 2015), suggesting glycation, an unavoidable age-associated process, might play a role in PD. A similar staining pattern of AGEs was reported in early Lewy bodies in patients with Lewy body disease This suggested that an excess of carbonyl compounds could play a role in the pathogenesis of PD (Munch et al, 2000). In hyperglycemia conditions and in diabetic patients, MGO is increased leading to higher
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