GBA1 mutations alter neuronal excitability and ultrastructure in Parkinson´s disease, regulating VGLUT2 and CRYAB in dopaminergic neurons DOI Creative Commons
Eva Rodríguez‐Traver, Luz M. Suárez, Carlos Crespo

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract Mutations in the glucocerebrosidase 1 (GBA1) gene are major risk factors for Parkinson´s disease (PD), but their role PD etiopathology is not fully understood. The impact of GBA1 mutations on neuronal maturation, function and degeneration was investigated dopaminergic (DA) neurons obtained from induced pluripotent stem cells (iPS cells/iPSCs) derived patients carrying heterozygous N370S or L444P mutation GBA1. DA co-expressing TH VGLUT2 were detected cultures, number and/or expression VGLUT2/SLC17A6 mRNA markedly reduced both cultures compared to controls. Electrophysiological recordings revealed a significant increase firing rate neurons, whereas evoked dopamine release stronger either than Furthermore, there accumulation α-synuclein aggregates cell body dendrites neurons. Remarkably, accumulated abundant Lewy body-like inclusions, multilamellar bodies, Golgi apparatus vacuolated dictyosomes autophagosomes. Notably, upregulation chaperone CRYAB/HSPB5/alpha-crystallin-B found early neuron differentiation substantia nigra patients. Therefore, our cellular model allows clear features neurodegeneration be Our findings indicate that impair midbrain expressing VGLUT2, provoke molecular, functional ultrastructural changes, possibly involved etiopathology. They suggest CRYAB may potentially serve as molecular targets biomarkers GBA1-PD.

Language: Английский

Single-nucleus multi-omics of Parkinson’s disease reveals a glutamatergic neuronal subtype susceptible to gene dysregulation via alteration of transcriptional networks DOI Creative Commons
E. Keats Shwab,

Daniel Gingerich,

Zhaohui Man

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: July 2, 2024

Abstract The genetic architecture of Parkinson’s disease (PD) is complex and multiple brain cell subtypes are involved in the neuropathological progression disease. Here we aimed to advance our understanding PD complexity at a subtype precision level. Using parallel single-nucleus (sn)RNA-seq snATAC-seq analyses simultaneously profiled transcriptomic chromatin accessibility landscapes temporal cortex tissues from 12 compared control subjects granular single resolution. An integrative bioinformatic pipeline was developed applied for these snMulti-omics datasets. results identified subpopulation cortical glutamatergic excitatory neurons with remarkably altered gene expression PD, including differentially-expressed genes within risk loci genome-wide association studies (GWAS). This only neuronal showing significant robust overexpression SNCA . Further characterization this neuronal-subpopulation showed upregulation specific pathways related axon guidance, neurite outgrowth post-synaptic structure, downregulated presynaptic organization calcium response. Additionally, characterized roles three molecular mechanisms governing PD-associated subtype-specific dysregulation expression: (1) changes cis-regulatory element transcriptional machinery; (2) abundance master regulators, YY1, SP3, KLF16; (3) candidate regulatory variants high linkage disequilibrium PD-GWAS genomic impacting transcription factor binding affinities. To knowledge, study first most comprehensive interrogation multi-omics landscape cell-subtype Our findings provide new insights into precise subtype, causal genes, non-coding underlying paving way development cell- gene-targeted therapeutics halt as well biomarkers early preclinical diagnosis.

Language: Английский

Citations

8
Revisiting the advance of age-dependent α-synuclein propagation and aggregation DOI Open Access
Dong‐Yan Song, Jiayi Li

Ageing and Neurodegenerative Diseases, Journal Year: 2025, Volume and Issue: 5(1)

Published: Feb. 22, 2025

Aging is a major risk factor for different neurodegenerative diseases (NDDs), including Parkinson’s disease (PD). In PD, one of the key neuropathological features cytoplasmic protein aggregation, named Lewy bodies (LBs) in cell body, and neurites (LNs) neuronal processes terminals. The α-synuclein (α-syn) has been found to be component LBs LNs, considered play central role their formation. α-Syn also increases healthy aging conditions. Evidence shown that promotes α-syn pathological aggregation propagation and, therefore, may induce aggravate PD pathogenesis. Here, we aim highlight recent advances age-related prion-like discuss subsequent consequences functions.

Language: Английский

Citations

0
Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations DOI Open Access
Paola Lenzi, Gloria Lazzeri, Michela Ferrucci

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3929 - 3929

Published: April 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

Language: Английский

Citations

2
GBA1MUTATIONS ALTER THE PHENOTYPE AND BEHAVIOUR OF DOPAMINERGIC NEURONS IN PARKINSON’S DISEASE, INFLUENCINGVGLUT2ANDCRYABEXPRESSION DOI Open Access
Eva Rodríguez‐Traver, Luz M. Suárez, Carlos Crespo

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 7, 2024

Abstract Mutations in the GBA1 gene are major risk factors for Parkinsońs disease (PD), but their role PD pathology is not fully understood. The impact of mutations was investigated dopamine (DA) neurons obtained from induced pluripotent stem cells (iPSCs) derived patients carrying N370S or L444P mutation. DA co-expressing TH and VGLUT2 were detected cultures, number and/or expression / SLC17A6 mRNA markedly reduced both cultures compared to controls. A significant increase firing rate found, whereas evoked release stronger either Furthermore, mutant accumulated abundant degenerative structures, there a accumulation α-synuclein aggregates neurons. Notably, upregulation chaperone CRYAB/HSPB5/alpha-crystallin-B found early neuron differentiation substantia nigra patients. Our findings indicate that impair midbrain expressing VGLUT2, provoke molecular, functional structural changes, possibly involved pathology.

Language: Английский

Citations

0
GBA1 mutations alter neuronal excitability and ultrastructure in Parkinson´s disease, regulating VGLUT2 and CRYAB in dopaminergic neurons DOI Creative Commons
Eva Rodríguez‐Traver, Luz M. Suárez, Carlos Crespo

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 16, 2024

Abstract Mutations in the glucocerebrosidase 1 (GBA1) gene are major risk factors for Parkinson´s disease (PD), but their role PD etiopathology is not fully understood. The impact of GBA1 mutations on neuronal maturation, function and degeneration was investigated dopaminergic (DA) neurons obtained from induced pluripotent stem cells (iPS cells/iPSCs) derived patients carrying heterozygous N370S or L444P mutation GBA1. DA co-expressing TH VGLUT2 were detected cultures, number and/or expression VGLUT2/SLC17A6 mRNA markedly reduced both cultures compared to controls. Electrophysiological recordings revealed a significant increase firing rate neurons, whereas evoked dopamine release stronger either than Furthermore, there accumulation α-synuclein aggregates cell body dendrites neurons. Remarkably, accumulated abundant Lewy body-like inclusions, multilamellar bodies, Golgi apparatus vacuolated dictyosomes autophagosomes. Notably, upregulation chaperone CRYAB/HSPB5/alpha-crystallin-B found early neuron differentiation substantia nigra patients. Therefore, our cellular model allows clear features neurodegeneration be Our findings indicate that impair midbrain expressing VGLUT2, provoke molecular, functional ultrastructural changes, possibly involved etiopathology. They suggest CRYAB may potentially serve as molecular targets biomarkers GBA1-PD.

Language: Английский

Citations

0