α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.

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Parkinson's Disease

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch012 ◽

2019 ◽

pp. 252-273 ◽

Cited By ~ 1

Author(s):

Vaibhav Walia ◽

Ashish Gakkhar ◽

Munish Garg

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Dopaminergic Neurons ◽

Older Patients ◽

Neurodegenerative Disorder ◽

Progressive Loss ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

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Found in Translation: The Utility of C. elegans Alpha-Synuclein Models of Parkinson’s Disease

Brain Sciences ◽

10.3390/brainsci9040073 ◽

2019 ◽

Vol 9 (4) ◽

pp. 73 ◽

Cited By ~ 7

Author(s):

Anthony Gaeta ◽

Kim Caldwell ◽

Guy Caldwell

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Alpha Synuclein ◽

Dopamine Neurons ◽

Genetic Modifiers ◽

Transgenic Expression ◽

C Elegans ◽

Dopaminergic Neurodegeneration ◽

Cellular Phenotypes ◽

Functional Mechanisms

Parkinson’s Disease (PD) is the second-most common neurodegenerative disease in the world, yet the fundamental and underlying causes of the disease are largely unknown, and treatments remain sparse and impotent. Several biological systems have been employed to model the disease but the nematode roundworm Caenorhabditis elegans (C. elegans) shows unique promise among these to disinter the elusive factors that may prevent, halt, and/or reverse PD phenotypes. Some of the most salient of these C. elegans models of PD are those that position the misfolding-prone protein alpha-synuclein (α-syn), a hallmark pathological component of PD, as the primary target for scientific interrogation. By transgenic expression of human α-syn in different tissues, including dopamine neurons and muscle cells, the primary cellular phenotypes of PD in humans have been recapitulated in these C. elegans models and have already uncovered multifarious genetic factors and chemical compounds that attenuate dopaminergic neurodegeneration. This review describes the paramount discoveries obtained through the application of different α-syn models of PD in C. elegans and highlights their established utility and respective promise to successfully uncover new conserved genetic modifiers, functional mechanisms, therapeutic targets and molecular leads for PD with the potential to translate to humans.

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What Is the Evidence that Parkinson’s Disease Is a Prion Disorder, Which Originates in the Gut?

International Journal of Molecular Sciences ◽

10.3390/ijms19113573 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3573 ◽

Cited By ~ 12

Author(s):

Małgorzata Kujawska ◽

Jadwiga Jodynis-Liebert

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Neurodegenerative Disorder ◽

Human Subjects ◽

Gastrointestinal Symptoms ◽

Convincing Evidence ◽

Substantia Nigra Pars Compacta ◽

Motor Nucleus ◽

The Brain

Parkinson’s disease (PD) is a neurodegenerative disorder resulting from degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). PD is characterized by motor dysfunctions as well as gastrointestinal symptoms and mental impairment. The pathological hallmark of PD is an accumulation of misfolded α-synuclein aggregates within the brain. The etiology of PD and related synucleinopathy is poorly understood, but recently, the hypothesis that α-synuclein pathology spreads in a prion-like fashion originating in the gut has gained much scientific attention. A crucial clue was the appearance of constipation before the onset of motor symptoms, gut dysbiosis and synucleinopathy in PD patients. Another line of evidence, demonstrating accumulation of α-synuclein within the peripheral autonomic nervous system (PANS), including the enteric nervous system (ENS), and the dorsal motor nucleus of the vagus (DMV) support the concept that α-synuclein can spread from the ENS to the brain by the vagus nerve. The decreased risk of PD following truncal vagotomy supports this. The convincing evidence of the prion-like behavior of α-synuclein came from postmortem observations that pathological α-synuclein inclusions appeared in healthy grafted neurons. In this review, we summarize the available data from human subjects’ research and animal experiments, which seem to be the most suggestive for explaining the hypotheses.

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Antioxidant and anti-inflammatory effects of dexrazoxane on dopaminergic neuron degeneration in rodent models of Parkinson's disease

Neuropharmacology ◽

10.1016/j.neuropharm.2019.107758 ◽

2019 ◽

Vol 160 ◽

pp. 107758 ◽

Cited By ~ 4

Author(s):

Meng Mei ◽

Yuanzhang Zhou ◽

Mengdi Liu ◽

Fangfang Zhao ◽

Cong Wang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neuron ◽

Rodent Models ◽

Neuron Degeneration ◽

Anti Inflammatory

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Heterogeneity of Incipient Atrophy Patterns in Parkinson’s Disease

10.1101/466086 ◽

2018 ◽

Author(s):

Pedro D. Maia ◽

Sneha Pandya ◽

Justin Torok ◽

Ajay Gupta ◽

Yashar Zeighami ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Neurodegenerative Disorder ◽

Neuronal Loss ◽

High Variability ◽

Clinical Value ◽

Optimization Routine ◽

Penalized Optimization ◽

The Brain

AbstractParkinson’s Disease (PD) is a the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by cell death in the amygdala and in substructures of the basal ganglia such as the substantia nigra. Since neuronal loss in PD leads to measurable atrophy patterns in the brain, there is clinical value in understanding where exactly the pathology emerges in each patient and how incipient atrophy relates to the future spread of disease. A recent seed-inference algorithm combining an established network-diffusion model with an L1-penalized optimization routine led to new insights regarding the non-stereotypical origins of Alzheimer’s pathologies across individual subjects. Here, we leverage the same technique to PD patients, demonstrating that the high variability in their atrophy patterns also translates into heterogeneous seed locations. Our individualized seeds are significantly more predictive of future atrophy than a single seed placed at the substantia nigra or the amygdala. We also found a clear distinction in seeding patterns between two PD subgroups – one characterized by predominant involvement of brainstem and ventral nuclei, and the other by more widespread frontal and striatal cortices. This might be indicative of two distinct etiological mechanisms operative in PD. Ultimately, our methods demonstrate that the early stages of the disease may exhibit incipient atrophy patterns that are more complex and variable than generally appreciated.

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Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration

Science Signaling ◽

10.1126/scisignal.abg3555 ◽

2021 ◽

Vol 14 (693) ◽

pp. eabg3555

Author(s):

Qinfang Liu ◽

Judith Bautista-Gomez ◽

Daniel A. Higgins ◽

Jianzhong Yu ◽

Yulan Xiong

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Adaptor Protein ◽

Endocytic Trafficking ◽

Dopaminergic Neurodegeneration ◽

Lrrk2 G2019s ◽

Endocytic Machinery ◽

Mutant Lrrk2 ◽

The Brain

Mutations in the kinase LRRK2 and impaired endocytic trafficking are both implicated in the pathogenesis of Parkinson’s disease (PD). Expression of the PD-associated LRRK2 mutant in mouse dopaminergic neurons was shown to disrupt clathrin-mediated endocytic trafficking. Here, we explored the molecular mechanism linking LRRK2 to endocytosis and found that LRRK2 bound to and phosphorylated the μ2 subunit of the adaptor protein AP2 (AP2M1), a core component of the clathrin-mediated endocytic machinery. Analysis of human SH-SY5Y cells and mouse neurons and tissues revealed that loss of LRRK2 abundance or kinase function resulted in decreased phosphorylation of AP2M1, which is required for the initial formation of clathrin-coated vesicles (CCVs). In contrast, overexpression of LRRK2 or expression of a Parkinson’s disease–associated gain-of-function mutant LRRK2 (G2019S) inhibited the uncoating of AP2M1 from CCVs at later stages and prevented new cycles of CCV formation. Thus, the abundance and activity of LRRK2 must be calibrated to ensure proper endocytosis. Dysregulated phosphorylation of AP2M1 from the brain but not thyroid tissues of LRRK2 knockout and G2019S-knockin mice suggests a tissue-specific regulatory mechanism of endocytosis. Furthermore, we found that LRRK2-dependent phosphorylation of AP2M1 mediated dopaminergic neurodegeneration in a Drosophila model of PD. Together, our findings provide a mechanistic link between LRRK2, AP2, and endocytosis in the pathogenesis of PD.

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α-synuclein pathogenesis in hiPSC models of Parkinson’s Disease

Neuronal Signaling ◽

10.1042/ns20210021 ◽

2021 ◽

Author(s):

Leo R Quinlan ◽

Jara Maria Baena-Montes ◽

Sahar Avazzadeh

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Modeling ◽

Viral Vector ◽

Neurodegenerative Disorder ◽

Current Knowledge ◽

Lewy Bodies ◽

Model Systems ◽

The Brain

α-synuclein is an increasingly prominent player in the pathology of a variety of neurodegenerative conditions. Parkinson’s disease (PD) is a neurodegenerative disorder that affects mainly the dopaminergic neurons in the substantia nigra of the brain. Typical of PD pathology is the finding of protein aggregations termed ‘Lewy bodies’ in the brain regions affected. α-synuclein is implicated in many disease states including dementia with Lewy bodies and Alzheimer’s disease. However, PD is the most common synucleinopathy and continues to be a significant focus of PD research in terms of the α-synuclein Lewy body pathology. Mutations in several genes are associated with PD development including SNCA, which encodes α-synuclein. A variety of model systems have been employed to study α-synuclein physiology and pathophysiology in an attempt to relate more closely to PD pathology. These models include cellular and animal system exploring transgenic technologies, viral vector expression and knockdown approaches, and models to study the potential prion protein-like effects of α-synuclein. The current review focuses on human induced pluripotent stem cell (iPSC) models with a specific focus on mutations or multiplications of the SNCA gene. iPSCs are a rapidly evolving technology with huge promise in the study of normal physiology and disease modeling in vitro. The ability to maintain a patient's genetic background and replicate similar cell phenotypes make iPSCs a powerful tool in the study of neurological diseases. This review focus on the current knowledge about α-synuclein physiological function as well as its role in PD pathogenesis based on human iPSC models.

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