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Escherichia coli triggers α-synuclein pathology in the LRRK2 transgenic mouse model of PD.

ABSTRACT: Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of LRRK2 risk variants are still unknown. Here, we report that a markedly increased abundance of Escherichia coli (E. coli) in the intestinal microbiota was detected in LRRK2 risk variant(R1628P or G2385R) carriers with sPD compared with carriers without sPD. Animal experiments showed that E. coli administration triggered pathological α-syn accumulation in the colon and spread to the brain via the gut-brain axis in Lrrk2 R1628P mice, due to the co-occurrence of Lrrk2 variant-induced inhibition of α-syn autophagic degradation and increased phosphorylation of α-syn caused by curli in E. coli-derived extracellular vesicles. Fecal microbiota transplantation (FMT) effectively ameliorated motor deficits and α-syn pathology in Lrrk2 R1628P mice. Our findings elaborate on the mechanism that E. coli triggers α-syn pathology in Lrrk2 R1628P mice, and highlight a novel gene-environment interaction pattern in LRRK2 risk variants. Even more importantly, the findings reveal the interplay between the specific risk gene and the matched environmental factors triggers the initiation of α-syn pathology in sPD.

SUBMITTER: Liang D

PROVIDER: S-EPMC10730176 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Escherichia coli triggers α-synuclein pathology in the LRRK2 transgenic mouse model of PD.

Liang Dongxiao D Liu Han H Jin Ruoqi R Feng Renyi R Wang Jiuqi J Qin Chi C Zhang Rui R Chen Yongkang Y Zhang Jingwen J Teng Junfang J Tang Beisha B Ding Xuebing X Wang Xuejing X

Gut microbes 20231127 2

Alpha-synuclein (α-syn) pathology is the hallmark of Parkinson's disease (PD). The leucine-rich repeat kinase 2 (LRRK2) gene is a major-effect risk gene for sporadic PD (sPD). However, what environmental factors may trigger the formation of α-syn pathology in carriers of LRRK2 risk variants are still unknown. Here, we report that a markedly increased abundance of Escherichia coli (E. coli) in the intestinal microbiota was detected in LRRK2 risk variant(R ...[more]

PMID: 38010914

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Project description:Previous studies demonstrate that intrastriatal injections of fibrillar alpha-synuclein (α-syn) into mice induce Parkinson's disease (PD)-like Lewy body (LB) pathology formed by aggregated α-syn in anatomically interconnected regions and significant nigrostriatal degeneration. The aim of the current study was to evaluate whether exogenous mouse α-syn pre-formed fibrils (PFF) injected into the striatum of rats would result in accumulation of LB-like intracellular inclusions and nigrostriatal degeneration. Sprague-Dawley rats received unilateral intrastriatal injections of either non-fibrillized recombinant α-syn or PFF mouse α-syn in 1- or 2- sites and were euthanized at 30, 60 or 180 days post-injection (pi). Both non-fibrillized recombinant α-syn and PFF α-syn injections resulted in phosphorylated α-syn intraneuronal accumulations (i.e., diffuse Lewy neurite (LN)- and LB-like inclusions) with significantly greater accumulations following PFF injection. LB-like inclusions were observed in several areas that innervate the striatum, most prominently the frontal and insular cortices, the amygdala, and the substantia nigra pars compacta (SNpc). α-Syn accumulations co-localized with ubiquitin, p62, and were thioflavin-S-positive and proteinase-k resistant, suggesting that PFF-induced pathology exhibits properties similar to human LBs. Although α-syn inclusions within the SNpc remained ipsilateral to striatal injection, we observed bilateral reductions in nigral dopamine neurons at the 180-day time-point in both the 1- and 2-site PFF injection paradigms. PFF injected rats exhibited bilateral reductions in striatal dopaminergic innervation at 60 and 180 days and bilateral decreases in homovanillic acid; however, dopamine reduction was observed only in the striatum ipsilateral to PFF injection. Although the level of dopamine asymmetry in PFF injected rats at 180 days was insufficient to elicit motor deficits in amphetamine-induced rotations or forelimb use in the cylinder task, significant disruption of ultrasonic vocalizations was observed. Taken together, our findings demonstrate that α-syn PFF are sufficient to seed the pathological conversion and propagation of endogenous α-syn to induce a progressive, neurodegenerative model of α-synucleinopathy in rats.

Project description:Alpha-synuclein pathology is associated with dopaminergic neuronal loss in the substantia nigra (SN) of Parkinson's patients. Working across human and mouse models, we investigated mechanisms by which the accumulation of soluble α-synuclein oligomers leads to neurodegeneration. Biochemical analysis of the midbrain of α-synuclein overexpressing BAC-transgenic male and female mice revealed age- and region-dependent mitochondrial dysfunction and accumulation of damaged proteins downstream of the RE1 Silencing Transcription Factor (REST). Vulnerable SN dopaminergic neurons displayed low REST levels compared with neighboring protected SN GABAergic neurons, which correlated with the accumulation of α-synuclein oligomers and disrupted mitochondrial morphology. Consistent with a protective role, REST levels were reduced in patient induced pluripotent stem cell-derived dopaminergic neurons carrying the SNCA-Triplication mutation, which accumulated α-synuclein oligomers and mitochondrial damage, and displayed REST target gene dysregulation. Furthermore, CRISPR-mediated REST KO induced mitochondrial dysfunction and impaired mitophagy in vitro Conversely, REST overexpression attenuated mitochondrial toxicity and mitochondrial morphology disruption through the transcription factor PGC-1α. Finally, decreased α-synuclein oligomer accumulation and mitochondrial dysfunction in mice correlated with nuclear REST and PGC-1α in protected SN GABAergic neurons compared with vulnerable dopaminergic neurons. Our findings show that increased levels of α-synuclein oligomers cause dopaminergic neuronal-specific dysfunction through mitochondrial toxicity, which can be attenuated by REST in an early model of Parkinsonian pathology. These findings highlight REST as a mediator of dopaminergic vulnerability in PD.SIGNIFICANCE STATEMENT Understanding early Parkinsonian pathophysiology through studies of advanced preclinical models is fundamental to the translation of disease-modifying therapies. Here we show disease-relevant levels of α-synuclein expression in mice leads to accumulation of α-synuclein oligomers in the absence of overt aggregation, and mitochondrial dysfunction in dopaminergic neurons lacking the RE1 Silencing Transcription Factor. Our findings identify the mechanism of action of RE1 Silencing Transcription Factor and PGC-1α as mediators of dopaminergic vulnerability in α-synuclein BAC-transgenic mice and induced pluripotent stem cell-derived dopaminergic cultures, highlighting their potential as therapeutic targets.

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Escherichia coli triggers α-synuclein pathology in the LRRK2 transgenic mouse model of PD.

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<i>Escherichia coli</i> triggers α-synuclein pathology in the <i>LRRK2</i> transgenic mouse model of PD.

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