Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease DOI Creative Commons
Liam Horan-Portelance, Michiyo Iba, Dominic J. Acri

et al.

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

Published: Aug. 1, 2024

One of the unifying pathological hallmarks Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is presence misfolded, aggregated, often phosphorylated forms protein α-synuclein in neurons. α-Synuclein pathology appears select populations neurons throughout various cortical subcortical regions, little currently known about why some develop while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) a transgenic mouse model that overexpresses wild-type human (α-syn-tg) to evaluate patterns selective neuronal vulnerability pathology. By performing post-IST immunofluorescence for at Ser129 (pSyn), identified cell types cortex hippocampus were vulnerable or resistant developing pSyn Next, investigated transcriptional underpinnings observed using set custom probes detect genes involved processing toxicity. We expression kinase:substrate pair Plk2 , which phosphorylates Ser129, SNCA ( hSNCA ), as underlying Finally, performed differential gene analysis, comparing non-transgenic cells pSyn- pSyn+ α-syn- tg reveal changes downstream overexpression pathology, included pSyn-dependent alterations mitochondrial endolysosomal genes. This study provides comprehensive use case IST, yielding new biological insights into formation its effects PD/DLB model.

Language: Английский

Biomarker‐Based Approach to α‐Synucleinopathies: Lessons from Neuropathology DOI Creative Commons
Gábor G. Kovács, Lea T. Grinberg, Glenda M. Halliday

et al.

Movement Disorders, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 3, 2024

Language: Английский

Citations

4
Modulation of conformational integrity and aggregation propensity of α-synuclein by osmolytes: Implications in therapeutic intervention of Parkinson’s disease DOI
Ishfaq Ahmad Ahanger,

Ishfaq Bashir Hajam,

Owais Hassan Wani

et al.

Progress in molecular biology and translational science, Journal Year: 2025, Volume and Issue: unknown, P. 63 - 87

Published: Jan. 1, 2025

Language: Английский

Citations

0
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
Proximity proteomics reveals unique and shared pathological features between multiple system atrophy and Parkinson’s disease DOI Creative Commons
Solji Choi, Tyler Tittle, Rahul Barot

et al.

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: March 23, 2025

Abstract Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative diseases shared clinical pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) hallmarks synucleinopathies, which, for PD/DLB, found predominantly in neurons, whereas MSA, aggregates primarily oligodendroglia. It remains unclear whether the distinct presentations PD/DLB MSA manifestations unique or processes. Using in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compared aggregated αsyn-interactomes (BAR-PSER129) total (BAR-MJFR1) between (n = 5) 10) forebrain midbrain structures. Comparison PD/DLB-enriched proteins revealed 79 PD/DLB-differentially abundant only three MSA-differentially (CBR1, CRYAB, GFAP). Pathway enrichment analysis that vesicle/SNARE-associated pathways dominated interactions, was strongly enriched metabolic/catabolic, iron, cellular oxidant detoxification pathways. A subnetwork cytosolic antioxidant enzymes called peroxiredoxins drove pathway MSA. network 26 proteins, including neuronal-specific (e.g., SYNGR3) HSPA8 core, DLB/PD. Extracellular exosome were universally regardless BAR target protein. In conclusion, synucleinopathies have divergent convergent αsyn-aggregate indicating pathogenic mechanisms. uniquely involves processes glial cells, while vesicular neurons dominate PD/DLB. Shared specifically SYNGR3, suggest neuronal axons origin both diseases. provide αsyn protein interaction maps two synucleinopathies.

Language: Английский

Citations

0
Current insights and assumptions on α-synuclein in Lewy body disease DOI Creative Commons
Rehana K. Leak,

Rachel N. Clark,

Muslim Abbas

et al.

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 148(1)

Published: Aug. 14, 2024

Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although aggregates only one component and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation pathology within across cells. Genetic mutations, genomic multiplications, sequence polymorphisms gene encoding also causally linked disease. In nonfamilial cases disease, disease trigger remains unidentified but may range from industrial/agricultural toxicants natural sources poisons microbial pathogens. Perhaps due these peripheral exposures, appear at early stages in brain regions connected with cranial nerves I X, which interface inhaled ingested environmental elements nasal or gastrointestinal cavities. Irrespective its identity, a stealthy most likely shifts soluble (directly indirectly) into insoluble, cross-β-sheet Indeed, β-sheet-rich self-replicating multimers reside patient plasma, cerebrospinal fluid, other tissues, can be subjected amplification assays. Thus, clinicians should able capitalize on assays stratify patients potential responders versus non-responders future clinical trials targeted therapies. Here, we briefly review current understanding speculate pathophysiological processes underlying transmission α-synucleinopathy neuraxis.

Language: Английский

Citations

2
Comparing alpha-synuclein-interactomes between multiple systems atrophy and Parkinsons disease reveals unique and shared pathological features. DOI Creative Commons
Solji Choi, Tyler Tittle, Rahul Barot

et al.

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

Published: Sept. 21, 2024

Abstract Introduction Primary synucleinopathies, such as Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are neurodegenerative disorders some shared clinical pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) the hallmark which for PD/DLB found predominantly in neurons (Neuronal cytoplasmic inclusions “NCIs”), but MSA, aggregates primarily oligodendroglia (Glial “GCIs”). It remains unclear if distinct presentation MSA manifestations or processes. We hypothesize that synucleinopathies share common molecular Methods Using in-situ proximity labeling technique biotinylation by antibody recognition (BAR), we compare aggregated αsyn-interactomes (BAR-PSER129) total (BAR-MJFR1) between (n=5) (n=10) forebrain midbrain structures. Results For BAR-PSER129 BAR-MJFR1 captures, αsyn was most significantly enriched protein MSA. In PD/DLB, identified 194 αsyn-aggregate-interacting proteins, while 245 interacting proteins. contrast, brain, only 38 175 proteins were each capture, respectively. When comparing a high overlap (59.5%) observed captured whereas less (14.4%) BAR-PSER129. Direct comparison revealed 79 PD/DLB-associated three MSA-associated (CBR1, CRYAB, GFAP). Pathway enrichment analysis interactions dominated vesicle/SNARE-associated pathways, contrast to strongly metabolic/catabolic, iron, cellular oxidant detoxification pathways. A subnetwork cytosolic antioxidant enzymes called peroxiredoxins drove pathways network 26 including neuronal-specific (e.g., SNYGR3) HSPA8 core, DLB/PD. Extracellular exosome universally regardless BAR target protein. Conclusion Synucleinopathies have divergent convergent αsyn-aggregate interactions, indicating unique pathogenic mechanisms. uniquely involves processes glial cells, vesicular dominate PD/DLB. Shared specifically SNYGR3 (i.e., neuronal protein), suggest axons origin both diseases. conclusion, provide interaction maps two synucleinopathies.

Language: Английский

Citations

1
Association between the Amplification Parameters of the α‐Synuclein Seed Amplification Assay and Clinical and Genetic Subtypes of Parkinson's Disease DOI Creative Commons
Piergiorgio Grillo, Luis Concha‐Marambio, Antonio Pisani

et al.

Movement Disorders, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

α-Synuclein seed amplification assay on cerebrospinal fluid (CSF-αSyn-SAA) has shown high accuracy for Parkinson's disease (PD) diagnosis. The analysis of CSF-αSyn-SAA parameters may provide useful insight to dissect the heterogeneity synucleinopathies.

Language: Английский

Citations

1
Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease DOI Creative Commons
Liam Horan-Portelance, Michiyo Iba, Dominic J. Acri

et al.

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

Published: Aug. 1, 2024

One of the unifying pathological hallmarks Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is presence misfolded, aggregated, often phosphorylated forms protein α-synuclein in neurons. α-Synuclein pathology appears select populations neurons throughout various cortical subcortical regions, little currently known about why some develop while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) a transgenic mouse model that overexpresses wild-type human (α-syn-tg) to evaluate patterns selective neuronal vulnerability pathology. By performing post-IST immunofluorescence for at Ser129 (pSyn), identified cell types cortex hippocampus were vulnerable or resistant developing pSyn Next, investigated transcriptional underpinnings observed using set custom probes detect genes involved processing toxicity. We expression kinase:substrate pair Plk2 , which phosphorylates Ser129, SNCA ( hSNCA ), as underlying Finally, performed differential gene analysis, comparing non-transgenic cells pSyn- pSyn+ α-syn- tg reveal changes downstream overexpression pathology, included pSyn-dependent alterations mitochondrial endolysosomal genes. This study provides comprehensive use case IST, yielding new biological insights into formation its effects PD/DLB model.

Language: Английский

Citations

0