Parkinson's disease-associated Pink1 loss disrupts vesicle trafficking in ensheathing glia causing dopaminergic neuron synapse loss DOI Creative Commons

Lorenzo Ghezzi,

Ulrike Pech, Nils Schoovaerts

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

ABSTRACT Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in substantia nigra , but many other cell types are affected even before neuron occurs. Recent studies have linked oligodendrocytes to early stages PD, though their precise role still unclear. Pink1 mutated familial PD and through unbiased single-cell sequencing entire brain Drosophila models, we observed significant gene deregulation ensheathing glia (EG); cells that share functional similarities oligodendrocytes. We found leads activation EG, similar reactive response EG seen upon nerve injury. Using cell-type specific transcriptomics, identified deregulated genes as potential modifiers. Specifically, downregulating two trafficking factors, Rab7 Vps13, also or direct regulators Rab7, Mon1 Ccz1, specifically was sufficient rescue neuronal function protect against synapse loss. Our findings demonstrate triggers an injury turn disrupts function. Vesicle components, which regulate membrane interactions between organelles within play a crucial maintaining health preventing work highlights essential glial support pathogenesis identifies vesicle these key point convergence progression.

Язык: Английский

Parkinson’s disease-associated Pink1 loss disrupts vesicle trafficking in Ensheathing glia causing dopaminergic neuron synapse loss DOI Open Access

Lorenzo Ghezzi,

Ulrike Pech, Nils Schoovaerts

и другие.

Опубликована: Фев. 17, 2025

Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in substantia nigra , but many other cell types are affected even before neuron occurs. Recent studies have linked oligodendrocytes to early stages PD, though their precise role still unclear. Pink1 mutated familial PD and through unbiased single-cell sequencing entire brain Drosophila models, we observed significant gene deregulation ensheathing glia (EG); cells that share functional similarities oligodendrocytes. We found leads activation EG, similar reactive response EG seen upon nerve injury. Using cell-type specific transcriptomics, identified deregulated genes as potential modifiers. Specifically, downregulating two trafficking factors, Rab7 Vps13, also or direct regulators Rab7, Mon1 Ccz1, specifically was sufficient rescue neuronal function protect against synapse loss. Our findings demonstrate triggers an injury turn disrupts function. Vesicle components, which regulate membrane interactions between organelles within play a crucial maintaining health preventing work highlights essential glial support pathogenesis identifies vesicle these key point convergence progression.

Язык: Английский

Процитировано

1
Parkinson’s disease-associated Pink1 loss disrupts vesicle trafficking in Ensheathing glia causing dopaminergic neuron synapse loss DOI Open Access

Lorenzo Ghezzi,

Ulrike Pech, Nils Schoovaerts

и другие.

Опубликована: Фев. 17, 2025

Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in substantia nigra , but many other cell types are affected even before neuron occurs. Recent studies have linked oligodendrocytes to early stages PD, though their precise role still unclear. Pink1 mutated familial PD and through unbiased single-cell sequencing entire brain Drosophila models, we observed significant gene deregulation ensheathing glia (EG); cells that share functional similarities oligodendrocytes. We found leads activation EG, similar reactive response EG seen upon nerve injury. Using cell-type specific transcriptomics, identified deregulated genes as potential modifiers. Specifically, downregulating two trafficking factors, Rab7 Vps13, also or direct regulators Rab7, Mon1 Ccz1, specifically was sufficient rescue neuronal function protect against synapse loss. Our findings demonstrate triggers an injury turn disrupts function. Vesicle components, which regulate membrane interactions between organelles within play a crucial maintaining health preventing work highlights essential glial support pathogenesis identifies vesicle these key point convergence progression.

Язык: Английский

Процитировано

0
Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models DOI Open Access
Ulrike Pech, Jasper Janssens, Nils Schoovaerts

и другие.

Опубликована: Фев. 28, 2025

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to emergence issues, patients frequently experience non-motor symptoms, such as sense smell (hyposmia). cellular molecular bases for these early defects remain enigmatic. To explore this, we developed new collection five fruit fly models familial conducted single-cell RNA sequencing young brains models. Interestingly, cholinergic projection neurons most vulnerable cells genes associated with presynaptic function deregulated. Additional single nucleus three specific brain regions Parkinson’s disease confirms findings. Indeed, disturbances lead synaptic dysfunction, notably affecting olfactory crucial in flies. Correcting specifically interneurons flies or inducing signaling Parkinson mutant human induced vitro using nicotine, both rescue age-dependent neuron decline. Hence, our research uncovers one earliest indicators 5 different higher-order this contributes development hyposmia. Furthermore, shared pathways failure ultimately contribute later life.

Язык: Английский

Процитировано

0
Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across five fly Parkinsonism models DOI Creative Commons
Ulrike Pech, Jasper Janssens, Nils Schoovaerts

и другие.

eLife, Год журнала: 2025, Номер 13

Опубликована: Апрель 3, 2025

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to emergence issues, patients frequently experience non-motor symptoms, such as sense smell (hyposmia). cellular molecular bases for these early defects remain enigmatic. To explore this, we developed new collection five fruit fly models familial conducted single-cell RNA sequencing young brains models. Interestingly, cholinergic projection neurons most vulnerable cells, genes associated with presynaptic function deregulated. Additional single nucleus three specific brain regions Parkinson’s disease confirms findings. Indeed, disturbances lead synaptic dysfunction, notably affecting olfactory crucial in flies. Correcting specifically interneurons flies or inducing signaling Parkinson mutant human induced vitro using nicotine, both rescue age-dependent neuron decline. Hence, our research uncovers one earliest indicators different higher-order this contributes development hyposmia. Furthermore, shared pathways failure ultimately contribute later life.

Язык: Английский

Процитировано

0
Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models DOI Creative Commons
Ulrike Pech, Jasper Janssens, Nils Schoovaerts

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Март 11, 2023

Abstract The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to emergence issues, patients frequently experience non-motor symptoms, such as sense smell (hyposmia). cellular molecular bases for these early defects remain enigmatic. To explore this, we developed new collection five fruit fly models familial conducted single-cell RNA sequencing young brains models. Interestingly, cholinergic projection neurons most vulnerable cells genes associated with presynaptic function deregulated. Additional single nucleus three specific brain regions Parkinson’s disease confirms findings. Indeed, disturbances lead synaptic dysfunction, notably affecting olfactory crucial in flies. Correcting specifically interneurons flies or inducing signaling Parkinson mutant human induced vitro using nicotine, both rescue age-dependent neuron decline. Hence, our research uncovers one earliest indicators 5 different higher-order this contributes development hyposmia. Furthermore, shared pathways failure ultimately contribute later life.

Язык: Английский

Процитировано

5
Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models DOI Open Access
Ulrike Pech, Jasper Janssens, Nils Schoovaerts

и другие.

Опубликована: Июль 17, 2024

The classical diagnosis of Parkinsonism is based on motor symptoms that are the consequence nigrostriatal pathway dysfunction and reduced dopaminergic output. However, a decade prior to emergence issues, patients frequently experience non-motor symptoms, such as sense smell (hyposmia). cellular molecular bases for these early defects remain enigmatic. To explore this, we developed new collection five fruit fly models familial conducted single-cell RNA sequencing young brains models. Interestingly, cholinergic projection neurons most vulnerable cells genes associated with presynaptic function deregulated. Additional single nucleus three specific brain regions Parkinson’s disease confirms findings. Indeed, disturbances lead synaptic dysfunction, notably affecting olfactory crucial in flies. Correcting specifically interneurons flies or inducing signaling Parkinson mutant human induced vitro using nicotine, both rescue age-dependent neuron decline. Hence, our research uncovers one earliest indicators 5 different higher-order this contributes development hyposmia. Furthermore, shared pathways failure ultimately contribute later life.

Язык: Английский

Процитировано

1
Soma-centered control of synaptic autophagy by Rab39-regulated anterograde trafficking of Atg9 DOI Open Access
Ayse Kilic,

Dirk Vandekerkhove,

Sabine Kuenen

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

Presynaptic terminals can be located far from the neuronal cell body and are thought to independently regulate protein organelle turnover. In this work, we report a soma-centered mechanism that regulates autophagy-driven turnover at distant presynaptic in Drosophila. We show system is regulated by Rab39, whose human homolog mutated Parkinson's disease. Although Rab39 localized soma, its loss of function causes increased autophagy terminals, resulting faster synaptic neurodegeneration. Using large-scale unbiased genetic modifier screen, identified genes encoding cytoskeletal axonal organizing proteins, including Shortstop (Shot), as suppressors autophagy. demonstrate controls Shot- Unc104/KIF1a-mediated transport autophagy-related Atg9 vesicles synapses. Under starvation conditions, soma shifts localization endosomes lysosomes, thereby controlling availability for trafficking Our findings indicate Rab39-mediated orchestrates cross-compartmental abundance

Язык: Английский

Процитировано

1
Synaptic sabotage: How Tau and α-Synuclein undermine synaptic health DOI Open Access
Valerie Uytterhoeven, Patrik Verstreken, Eliana Nachman

и другие.

The Journal of Cell Biology, Год журнала: 2024, Номер 224(2)

Опубликована: Дек. 24, 2024

Synaptic dysfunction is one of the earliest cellular defects observed in Alzheimer's disease (AD) and Parkinson's (PD), occurring before widespread protein aggregation, neuronal loss, cognitive decline. While field has focused on aggregation Tau α-Synuclein (α-Syn), emerging evidence suggests that these proteins may drive presynaptic pathology even their aggregation. Therefore, understanding mechanisms by which α-Syn affect terminals offers an opportunity for developing innovative therapeutics aimed at preserving synapses potentially halting neurodegeneration. This review focuses molecular converge caused α-Syn. Both have physiological roles synapses. However, during disease, they acquire abnormal functions due to aberrant interactions mislocalization. We provide overview current research different essential pathways influenced Finally, we highlight promising therapeutic targets maintaining synaptic function both tauopathies synucleinopathies.

Язык: Английский

Процитировано

1
Parkinson's disease-associated Pink1 loss disrupts vesicle trafficking in ensheathing glia causing dopaminergic neuron synapse loss DOI Creative Commons

Lorenzo Ghezzi,

Ulrike Pech, Nils Schoovaerts

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

ABSTRACT Parkinson’s disease (PD) is commonly associated with the loss of dopaminergic neurons in substantia nigra , but many other cell types are affected even before neuron occurs. Recent studies have linked oligodendrocytes to early stages PD, though their precise role still unclear. Pink1 mutated familial PD and through unbiased single-cell sequencing entire brain Drosophila models, we observed significant gene deregulation ensheathing glia (EG); cells that share functional similarities oligodendrocytes. We found leads activation EG, similar reactive response EG seen upon nerve injury. Using cell-type specific transcriptomics, identified deregulated genes as potential modifiers. Specifically, downregulating two trafficking factors, Rab7 Vps13, also or direct regulators Rab7, Mon1 Ccz1, specifically was sufficient rescue neuronal function protect against synapse loss. Our findings demonstrate triggers an injury turn disrupts function. Vesicle components, which regulate membrane interactions between organelles within play a crucial maintaining health preventing work highlights essential glial support pathogenesis identifies vesicle these key point convergence progression.

Язык: Английский

Процитировано

0