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?-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits.

ABSTRACT: While studying transgenic mice that overexpress human wildtype alpha-synuclein (Thy1-ASO, ASO) for typical brain alpha-synucleinopathy and central nervous system neuropathology, we observed progressive functional changes in the gastrointestinal and other peripheral organs. A more systematic study revealed that the gastrointestinal tract in ASO mice showed severe distension and blockage of the large intestine by 9-12 months of age. Functional assessments demonstrated a reduction in fecal water content and fecal pellet output, and increased whole gut transit time, in ASO mice compared to wildtype littermates, indicative of constipation, a symptom commonly reported by Parkinson's disease (PD) patients. Food intake was increased and body weight was decreased in 12 month old ASO mice, suggestive of metabolic abnormalities. Post-mortem histological analyses showed that human alpha-synuclein protein was robustly expressed in axonal fibers and in occasional cell bodies of the enteric nervous system, and in the heart of ASO mice. Accumulation of proteinase-K insoluble alpha-synuclein, reminiscent of neurodegenerative processes in PD was also observed. The functional and pathological changes we document here in ASO mice could relate to the autonomic deficits also seen in idiopathic and alpha-synuclein-mediated genetic forms of PD. These experimental data provide a foundation for therapeutic modeling of autonomic changes in PD and related alpha-synucleinopathies.

SUBMITTER: Hallett PJ

PROVIDER: S-EPMC3376017 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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α-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits.

Hallett Penelope J PJ McLean Jesse R JR Kartunen Andrew A Langston J William JW Isacson Ole O

Neurobiology of disease 20120419 2

While studying transgenic mice that overexpress human wildtype alpha-synuclein (Thy1-ASO, ASO) for typical brain alpha-synucleinopathy and central nervous system neuropathology, we observed progressive functional changes in the gastrointestinal and other peripheral organs. A more systematic study revealed that the gastrointestinal tract in ASO mice showed severe distension and blockage of the large intestine by 9-12 months of age. Functional assessments demonstrated a reduction in fecal water co ...[more]

PMID: 22549133

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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.

Project description:Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a central regulator of cellular stress responses and its transcriptional activation promotes multiple cellular defense and survival mechanisms. The loss of NRF2 has been shown to increase oxidative and proteotoxic stress, two key pathological features of neurodegenerative disorders such as Parkinson's disease (PD). Moreover, compromised redox homeostasis and protein quality control can cause the accumulation of pathogenic proteins, including alpha-synuclein (α-Syn) which plays a key role in PD. However, despite this link, the precise mechanisms by which NRF2 may regulate PD pathology is not clear. In this study, we generated a humanized mouse model to study the importance of NRF2 in the context of α-Syn-driven neuropathology in PD. Specifically, we developed NRF2 knockout and wild-type mice that overexpress human α-Syn (hα-Syn+/Nrf2-/- and hα-Syn+/Nrf2+/+ respectively) and tested changes in their behavior through nest building, challenging beam, and open field tests at three months of age. Cellular and molecular alterations in α-Syn, including phosphorylation and subsequent oligomerization, as well as changes in oxidative stress, inflammation, and autophagy were also assessed across multiple brain regions. It was observed that although monomeric α-Syn levels did not change, compared to their wild-type counterparts, hα-Syn+/Nrf2-/- mice exhibited increased phosphorylation and oligomerization of α-Syn. This was associated with a loss of tyrosine hydroxylase expressing dopaminergic neurons in the substantia nigra, and more pronounced behavioral deficits reminiscent of early-stage PD, in the hα-Syn+/Nrf2-/- mice. Furthermore, hα-Syn+/Nrf2-/- mice showed significantly amplified oxidative stress, greater expression of inflammatory markers, and signs of increased autophagic burden, especially in the midbrain, striatum and cortical brain regions. These results support an important role for NRF2, early in PD progression. More broadly, it indicates NRF2 biology as fundamental to PD pathogenesis and suggests that targeting NRF2 activation may delay the onset and progression of PD.

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?-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits.

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α-Synuclein overexpressing transgenic mice show internal organ pathology and autonomic deficits.

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