Dataset Information

Interactions of Neurodegenerative Disease Positron Emission Tomography Imaging Probe Candidates with the C-Terminus of α-Synuclein Fibrils.

ABSTRACT: Fibrillar aggregation of α-synuclein (αS) is a hallmark of Parkinson's disease (PD) and related disorders, including multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Herein, the fibril interactions of two candidate positron emission tomography (PET) imaging ligands, M503 and HY-215, being developed for imaging of PD/DLB and MSA, respectively, are investigated. Photo-crosslinking mass spectrometry is used to determine the sites of their binding to in vitro fibrils, and Förster resonance energy transfer with fluorescently labeled proteins is used to analyze conformational changes in the disordered αS C-terminus. Taken together, these studies show that the MSA-selective PET lead, HY-215, interacts with the C-terminus, unlike the PD-selective lead M503. This study indicates that interactions with the often-ignored disordered regions of αS fibrils should be considered in the development of PET probes and other therapeutic small molecules.

SUBMITTER: Shaffer KD

PROVIDER: S-EPMC12631007 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature

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Interactions of Neurodegenerative Disease Positron Emission Tomography Imaging Probe Candidates with the C-Terminus of α-Synuclein Fibrils.

Shaffer Kyle D KD Perez Ryann M RM Lougee Marshall G MG Pagar Vinayak V VV Kim Hee Jong HJ Kim Ho Young HY Garcia Benjamin A BA Mach Robert H RH Petersson E James EJ

Chembiochem : a European journal of chemical biology 20251013 22

Fibrillar aggregation of α-synuclein (αS) is a hallmark of Parkinson's disease (PD) and related disorders, including multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). Herein, the fibril interactions of two candidate positron emission tomography (PET) imaging ligands, M503 and HY-215, being developed for imaging of PD/DLB and MSA, respectively, are investigated. Photo-crosslinking mass spectrometry is used to determine the sites of their binding to in vitro fibrils, and Förster r ...[more]

PMID: 41078085

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Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

Interactions of Neurodegenerative Disease Positron Emission Tomography Imaging Probe Candidates with the C-Terminus of α-Synuclein Fibrils.

Publications

Interactions of Neurodegenerative Disease Positron Emission Tomography Imaging Probe Candidates with the C-Terminus of α-Synuclein Fibrils.

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