Behavioral screening defines three molecular Parkinsonism subgroups in Drosophila

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

Опубликована: Авг. 27, 2024

Abstract Parkinsonism is defined by motor dysfunction, but the specific upstream molecular causes of these clinical symptoms can vary widely. We hypothesize that converge onto a limited number core cellular pathways. To investigate this, we created new collection 24 genetically very well-controlled animal models familial forms parkinsonism. Using unbiased behavioral screening and machine learning identified three clusters mutants on (1) mitochondrial function; (2) retromer/vesicle trafficking; (3) proteostasis/autophagy. Genes within each cluster have similar genetic interaction profile compounds target pathways ameliorate dopaminergic neuron dysfunction in cluster-specific manner. This suggests parkinsonism be stratified into broad functional groups our findings pave way for targeted biomarker discovery drug development.

Язык: Английский

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Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models

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 representing various forms familial conducted single-cell RNA sequencing young entire 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 recapitulates finding. Indeed, disturbances lead synaptic dysfunction, notably affecting olfactory crucial in flies. Our research uncovers one earliest indicators 5 different higher-order neurons, it suggests common pathways contribute development hyposmia.

Язык: Английский

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Developmental origins of Parkinson’s disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

Toxicological Sciences, Год журнала: 2024, Номер 201(2), С. 263 - 281

Опубликована: Июль 12, 2024

Abstract Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with an increased risk of Parkinson’s disease (PD). Animal support a link between developmental and neuronal susceptibility in α-synuclein preformed fibril MPTP models adult male C57BL/6 mice. In previous study, we showed was sex-specific changes DNA modifications within genes related dopaminergic neuron development maintenance at 12 wk age. Here, used capture hybridization-sequencing custom baits interrogate across entire genetic loci previously identified multiple time points—birth, 6, 12, 36 old. We largely dieldrin-induced each point annotated pathways important for neurodevelopment, potentially critical steps early differentiation, synaptogenesis, synaptic plasticity, glial–neuron interactions. Despite large numbers age-specific modifications, longitudinal analysis small number differential modification cytosines deflection epigenetic aging. The sex-specificity these results adds evidence responses PD-related exposures may underly differences disease. Overall, data idea leads patterns persist after period disrupt neurodevelopmental pathways, thereby impacting late-life diseases, including PD.

Язык: Английский

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Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models

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

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Carriers of LRRK2 pathogenic variants show a milder, anatomically distinct brain signature of Parkinson's disease

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Март 10, 2025

Abstract LRRK2 gene variants are a major genetic risk factor for both familial and sporadic Parkinson’s disease (PD), opening an unattended window on the disease’s mechanisms potential therapies. Investigating influence of pathogenic in brain structure is crucial step toward enabling early diagnosis personalized treatment. Yet, despite its significance, ways which genotype affects remain largely unexplored. Work this domain plagued by small sample sizes differences cohort composition, can obscure genuine distinctions among clinical subgroups. In study, we overcome such important limitations combining explicit modeling population background variation pattern matching. Specifically, leveraged large 641 participants (including 364 with PD diagnosis) to examine MRI-detectable cortical atrophy patterns associated people non-manifesting individuals. patients exhibited milder thinning compared PD, notable preservation temporal occipital regions, suggesting distinct neurodegeneration. Non-manifesting carriers showed no significant atrophy, indicating structural signs subclinical PD. We further analyzed relationship between aggregated alpha-synuclein cerebrospinal fluid atrophy. found that those evidence experienced pronounced neurodegeneration increased thinning, possibly defining another aggressive subtype. Our findings highlight avenues distinguishing subtypes, could lead more targeted treatment approaches complete understanding progression.

Язык: Английский

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Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across five fly Parkinsonism models

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

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Advances in Understanding Biomarkers and Treating Neurological Diseases -Role of the Cerebellar Dysfunction and Emerging Therapies

Ageing Research Reviews, Год журнала: 2024, Номер unknown, С. 102519 - 102519

Опубликована: Сен. 1, 2024

Язык: Английский

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Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3929 - 3929

Опубликована: Апрель 1, 2024

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on pathophysiology Parkinson’s disease (PD). line with this, alpha-syn considered to be guilty protein in process, it may targeted through precision medicine modify progression. Therefore, designing specific tools block aggregation spreading represents effort development disease-modifying therapies PD. The present article analyzes concrete evidence about significance within LBs. this effort, some dogmas are challenged. concerns question whether more abundant compared other proteins Again, occurrence non-protein constituents scrutinized. Finally, LBs causing PD questioned. These revisited concepts helpful process validating which proteins, organelles, pathways likely involved damage meso-striatal dopamine neurons brain regions

Язык: Английский

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Developmental origins of Parkinson’s disease risk: perinatal exposure to the organochlorine pesticide dieldrin leads to sex-specific DNA modifications in critical neurodevelopmental pathways in the mouse midbrain

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

Опубликована: Апрель 29, 2024

Epidemiological studies show that exposure to the organochlorine pesticide dieldrin is associated with increased risk of Parkinson's disease (PD). Animal support a link between developmental and neuronal susceptibility in α-synuclein preformed fibril (α-syn PFF) MPTP models adult male C57BL/6 mice. In previous study, we showed was sex-specific changes DNA modifications within genes related dopaminergic neuron development maintenance at 12 weeks age. Here, used capture hybridization-sequencing custom baits interrogate across entire genetic loci previously identified multiple time points - birth, 6 weeks, 36 old. We largely dieldrin-induced each point annotated pathways important for neurodevelopment, potentially critical steps early differentiation, synaptogenesis, synaptic plasticity, glial-neuron interactions. Despite large numbers age-specific modifications, longitudinal analysis small number DMCs deflection epigenetic aging. The sex-specificity these results adds evidence responses PD-related exposures may underly differences disease. Overall, data idea leads patterns persist after period disrupt neurodevelopmental pathways, thereby impacting late life diseases, including PD.

Язык: Английский

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Synaptic deregulation of cholinergic projection neurons causes olfactory dysfunction across 5 fly Parkinsonism models

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

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