Dataset Information

Impaired aldehyde detoxification exacerbates motor deficits in an alpha-synuclein mouse model of Parkinson's disease.

ABSTRACT:

Introduction

The discovery of biogenic aldehydes in the postmortem parkinsonian brain and the ability of these aldehydes to modify and cross-link proteins has called attention to their possible role in Parkinson's disease. For example, many in vitro studies have found that the aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), induces the formation of stable, neurotoxic alpha-synuclein oligomers.

Methods

To study this in vivo, mice deficient in the two aldehyde dehydrogenase enzymes (Aldh1a1 and Aldh2, DKO) primarily responsible for detoxification of DOPAL in the nigrostriatal pathway were crossed with mice that overexpress human wild-type alpha-synuclein. DKO overexpressing human wild-type alpha-synuclein (DKO/ASO) offspring were evaluated for impairment on motor tasks associated with Parkinsonism.

Results

DKO/ASO mice developed severe motor deficits greater than that of mice overexpressing human wild-type alpha-synuclein alone.

Conclusion

These results provide evidence to support the idea that biogenic aldehydes such as DOPAL interact with human wild-type alpha-synuclein, directly or indirectly, in vivo to exacerbate locomotor deficits in Parkinson's disease.

SUBMITTER: Martinez PA

PROVIDER: S-EPMC10498093 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Impaired aldehyde detoxification exacerbates motor deficits in an alpha-synuclein mouse model of Parkinson's disease.

Martinez Paul Anthony PA Martinez Vanessa Elia VE Rani Sheela S Murrell Meredith M Javors Martin M Gelfond Jonathan J Doorn Jonathan Alan JA Fernandez Elizabeth E Strong Randy R

Brain and behavior 20230714 9

<h4>Introduction</h4>The discovery of biogenic aldehydes in the postmortem parkinsonian brain and the ability of these aldehydes to modify and cross-link proteins has called attention to their possible role in Parkinson's disease. For example, many in vitro studies have found that the aldehyde metabolite of dopamine, 3,4-dihydroxyphenylacetaldehyde (DOPAL), induces the formation of stable, neurotoxic alpha-synuclein oligomers.<h4>Methods</h4>To study this in vivo, mice deficient in the two aldeh ...[more]

PMID: 37452461

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Project description:Decreased clearance of α-synuclein (aSyn) and aSyn protein misfolding and aggregation are seen as major factors in the pathogenesis of Parkinson's disease (PD) and other synucleinopathies that leads to disruption in neuronal function and eventually to cell death. Prolyl oligopeptidase (PREP) can accelerate the aSyn aggregation process, while inhibition of PREP by a small molecule inhibitor decreases aSyn oligomer formation and enhances its clearance via autophagy in different aSyn overexpressing cell types and in transgenic PD animal models. In this study, we investigated the impact of chronic PREP inhibition by a small molecule inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047), on aSyn oligomerization, clearance, and underlying spontaneous motor behavior in a virus vector-based aSyn overexpression mouse model 4 weeks after aSyn microinjections and after the onset of symptomatic forepaw bias. Following 4 weeks of PREP inhibition, we saw an improved spontaneous forelimb use in mice that correlated with a decreased immunoreactivity against oligomer-specific forms of aSyn. Additionally, KYP-2047 had a trend to enhance dopaminergic systems activity. Our results suggest that PREP inhibition exhibits a beneficial effect on the aSyn clearance and aggregation in a virus mediated aSyn overexpression PD mouse model and that PREP inhibitors could be a novel therapeutic strategy for synucleinopathies.Significance statementAlpha-synuclein (aSyn) has been implicated in Parkinson's disease, with aSyn aggregates believed to exert toxic effects on neurons, while prolyl oligopeptidase (PREP) has been shown to interact with aSyn both in cells and cell free conditions, thus enhancing its aggregation. We demonstrate the possibility to abolish motor imbalance caused by aSyn viral vector injection with chronic 4 week PREP inhibition by a potent small-molecule PREP inhibitor, 4-phenylbutanoyl-l-prolyl-2(S)-cyanopyrrolidine (KYP-2047). Treatment was initiated postsymptomatically, 4 weeks after aSyn injection. KYP-2047-treated animals had a significantly decreased amount of oligomeric aSyn particles and improved dopamine system activity compared to control animals. To our knowledge, this is the first time viral overexpression of aSyn has been countered and movement impairments abolished after their onset.

Dataset Information

Impaired aldehyde detoxification exacerbates motor deficits in an alpha-synuclein mouse model of Parkinson's disease.

Introduction

Methods

Results

Conclusion

Publications

Impaired aldehyde detoxification exacerbates motor deficits in an alpha-synuclein mouse model of Parkinson's disease.

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