α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Dagra, Abeer; Miller, Douglas R.; Lin, Min; Gopinath, Adithya; Shaerzadeh, Fatemeh; Harris, Sam; Sorrentino, Zachary A.; Støier, Jonatan Fullerton; Velasco, Sophia; Azar, Janelle; Alonge, Adetola R; Lebowitz, Joseph J.; Ulm, Brittany; Bu, Mengfei; Hansen, Carissa A.; Urs, Nikhil M.; Khoshbouei, Habibeh

doi:10.1038/s41531-021-00210-w

Cited by 26 publications

(17 citation statements)

References 166 publications

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“…Noteworthy, in line with the absence of other signs of degeneration, 23 the dendritic arbor of DA cells is preserved at an earlier time‐point (5‐month‐old Snca +/+ rats). Interestingly, a recent study in neuronal cultures of midbrain DA neurons also demonstrated that virally induced α‐syn–overexpressing neurons exhibit a lower degree of dendritic arborization compared with naive DA neurons 48 . Altogether, α‐syn–dependent somatodendritic alterations observed in aged Snca +/+ nigral DA neurons model the pathological changes of the DAergic system occurring in humans during PD progression 43,45‐47 and provide additional insights into the mechanisms by which α‐syn overload drives SNpc DA neurons' pathology.…”

Section: Discussionmentioning

confidence: 99%

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

et al. 2022

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Background: The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn-dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. Objectives: We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. Methods: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12-to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca +/+ ) and age-matched wild-type rats.Results: Aged Snca +/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/ inactivating voltage-gated K + channels and Ca 2+ -and voltage-activated large conductance K + channels. These intrinsic currents underlie the repolarization/ afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. Conclusions: Besides clarifying α-syn-induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

et al. 2022

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“…Another important feature highlighted in the present study is the dystrophic TH + dendritic arborizations, branching from SNpc surviving DAergic neurons towards the SNpr in LPS Snca +/+ rats, anticipating by almost seven months similar alterations in the naϊve Snca +/+ animals 21 . The loss of neuronal complexity and the decreased dendritic arborization have been linked to α-synuclein overexpression in virally infected DAergic neurons in vitro and in vivo , preceding their eventual death 34,35 and resembling PD patient’s post- mortem alterations 36 .…”

Section: Discussionmentioning

confidence: 99%

Systemic inflammation triggers long-lasting neuroinflammation and accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human α-synuclein

Massaro Cenere,

Tiberi,

Paldino

et al. 2024

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Increasing efforts have been made to elucidate how genetic and environmental factors interact in Parkinson's disease (PD). In the present study, we assessed the development of PD-like symptoms on a genetic PD rat model overexpressing human α-synuclein (Snca+/+) at a presymptomatic age, exposed to a pro-inflammatory insult by intraperitoneal injection of lipopolysaccharide (LPS), using immunohistology, high-dimensional flow cytometry, electrophysiology, and behavioral analyses. A single injection of LPS to both WT and Snca+/+ rats triggered long-lasting increased activation of pro-inflammatory microglial markers, infiltrating monocytes and T-lymphocytes. However, only LPS Snca+/+ rats displayed dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), associated with a reduction of evoked dopamine release in the striatum. No significant changes were observed in the behavioral domain. We propose our double-hit animal as a reliable model to investigate the mechanisms whereby α-synuclein and inflammation interact to promote neurodegeneration in PD.

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“…Our data showing dysregulation of dopamine release and genes related to dopamine synthesis suggests a possible association with α-Syn accumulation and calcium homeostasis. Overexpression of α-Syn has been shown to decrease the auto-inhibitory function of D2 receptors in DA neurons and increase intracellular and extracellular dopamine levels and tyrosine hydroxylase expression 53 . Furthermore, calcium has been shown to directly and indirectly increase α-Syn pathology [54][55][56] .…”

Section: Discussionmentioning

confidence: 99%

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

Fathi¹,

Bakshy²,

Zieghami³

et al. 2023

Preprint

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Multiple neurodegenerative disorders, including Parkinson,s disease (PD) and Alzheimer,s disease-associated dementia (ADAD), are linked with dopaminergic (DA) neuron death and a resulting reduction in dopamine levels in the brain. DA neuron degeneration and the risk of developing PD is connected to genetic mutations affiliated with lysosomal function and protein degradation. Accessible human cellular models for PD-relevant genetic mutations are needed to investigate mechanisms of DA cell death and define points of therapeutic intervention. Human induced pluripotent stem cell (iPSC)-derived midbrain DA neurons offer a developmentally and physiologically relevant in vitro model for investigating PD pathogenic mechanisms across genetic backgrounds. In this study, we generated DA neurons using iPSCs from two clinically diagnosed PD patients, one harboring an inherited GBAN370Smutation and the other a mutation in LRRK2G2019Sand compared pathophysiology against DA neurons from genetically engineered SNCAA53TiPSCs and its isogenic apparently healthy normal (AHN) iPSCs. Our results present a novel phenotype for GBAN370Sand LRRK2G2019Sderived DA neurons, showing that they produced and released significantly more dopamine compared to the AHN and SNCAA53Tmutant DA neurons. All mutant DA neurons developed deficient glucocerebrosidase (GCase) activity, increased mitochondrial stress, aberrant neuronal activity patterns, and increased α-synuclein accumulation. Together these data suggest potentially divergent origins of PD pathogenesis in GBAN370Sand LRRK2G2019SDA neurons. In addition, compound screening confirmed that GCase modulators can rescue enzyme activity and impact neural activity across all DA mutant neurons, to varying degrees. These data demonstrate unique in vitro phenotypes associated with PD and suggest a diversity of underlying mechanisms across different genetic backgrounds. Together, the cell lines used in this study present a valuable tool for new therapeutic discovery.

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α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Cited by 26 publications

References 166 publications

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

Systemic inflammation triggers long-lasting neuroinflammation and accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human α-synuclein

Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons

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α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

Cited by 26 publications

References 166 publications

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

Systemic inflammation triggers long-lasting neuroinflammation and accelerates neurodegeneration in a rat model of Parkinson’s disease overexpressing human α-synuclein

Diverging Parkinson’s Disease Pathology between patient-derivedGBAN370S, LRRK2G2019Sand engineeredSNCAA53TiPSC-derived Dopaminergic Neurons

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Diverging Parkinson’s Disease Pathology between patient-derivedGBA^N370S, LRRK2^G2019Sand engineeredSNCA^A53TiPSC-derived Dopaminergic Neurons