Biology subjects

Rosenthal, L. S.

Publications and source records attributed to Rosenthal, L. S..

3 recordsLinked to original sources

bioRxiv2024

α-Synuclein Strain Dynamics Correlate with Cognitive Shifts in Parkinson's Disease

-Synuclein (-syn) strains can serve as discriminators between Parkinsons disease (PD) and related -synucleinopathies. The relationship between -syn strain dynamics and clinical performance as patients transition from normal cognition (NC) to cognitive impairment (CI) is not known. Here, we show that the biophysical properties and neurotoxicity of -syn strains change as PD cognitive status transitions from NC to mild cognitive impairment (PD-MCI) and dementia (PD-D). Both cross-sectional and longitudinal analyses reveal distinct -syn strains in PD patients correlating to their level of cognitive impairment. Machine learning (ML) was employed to achieve high classification accuracy. The combination of thioflavin T (ThT) maximal fluorescence intensity (mfi), max slope of rise curve (forming rate), lag time (tlag), 20% time (t20), and half-time (t50), dynamic light scattering (DLS) (peak number, [1/2] peak size, [1/2] peak intensity) and neurotoxicity together with demographic variables for model training yielded superior performance (89[~]99% accuracy in the 4- and 2- classification schema) compared to individual features alone in classifying cognitive status. For the longitudinal study, DLS peak number emerged as the strongest predictor of cognitive transition (HR = 0.12, P = 0.002), with the optimal predictive model combining DLS peak number, sex, education, DLS peak 1 size, and DLS peak 2 polydispersity achieving high accuracy (C-index of [~]93%). This study presents evidence that individuals with PD have different -syn strains correlating to their cognitive status and highlights the potential of -syn strain dynamics to guide future diagnosis, management, and stratification of PD patients. One Sentence SummaryDistinct features of -syn strains change with cognitive decline in Parkinsons disease and AI-based analysis incorporating these combined characteristics serves as a powerful tool for PD clinical stratification.

neuroscience↗

bioRxiv2024

Pathologic α-Synuclein-NOD2 Interaction and RIPK2 Activation Drives Microglia-Induced Neuroinflammation in Parkinson's Disease

Pathological aggregation of -Synuclein (-Syn) and neuroinflammation are closely linked to Parkinsons disease (PD). However, the specific regulators of the neuroinflammation caused by pathological -syn remain obscure. In this study, we show that NOD2/RIPK2 signaling is a crucial regulator of neuroinflammation in PD. Pathological -syn binds to NOD2, causing self-oligomerization and complex formation with RIPK2, leading to RIPK2 ubiquitination and activation of MAPK and NF-kB. Notably, this NOD2/RIPK2 signaling is particularly active in microglia of human PD brains and the -Syn preformed fibril (-Syn PFF) mouse model. Depleting NOD2 or RIPK2 reduces neuroinflammation and protects against dopamine neuron degeneration in a pathologic -Syn mouse model by blocking the formation of neurotoxic reactive astrocytes caused by microglia activation. The discovery of NOD2/RIPK2 signaling as a key regulator of neuroinflammation in PD provides a new understanding of -Syn-driven neuroinflammation and neurodegeneration in PD and a potential new therapeutic strategy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/580982v2_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@10c010aorg.highwire.dtl.DTLVardef@1183b23org.highwire.dtl.DTLVardef@1d289dborg.highwire.dtl.DTLVardef@158b6ef_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefPathological -Synuclein (-Syn) binds to the microglial NOD2 protein, which in turn triggers NOD2/RIPK2 complex and RIPK2 phosphorylation/ubiquitination. This process activates the NF-kB/MAPK pathways, ultimately leading to neurotoxic reactive astrocyte-induced dopaminergic neurodegeneration. Depletion of RIPK2 (RIPK2 KO) or NOD2 (NOD2) protects dopamine neurons in a mouse model of Parkinsons disease (PD). These findings provide insights into -Syn-driven neuroinflammation and offer potential therapeutic strategies for PD. HighlightsNOD2/RIPK2 signaling is identified as a crucial regulator of neuroinflammation in PD. NOD2/RIPK2 signaling is highly active in microglia in human PD brains and -Syn PFF mouse models. Pathological -Syn binds to NOD2, triggering self-oligomerization and RIPK2 complex formation, leading to MAPK and NF-kB activation Genetic depletion of NOD2 or RIPK2 reduces neuroinflammation and protects dopamine neurons by blocking the formation of neurotoxic reactive astrocytes.

neuroscience↗

bioRxiv2023

Biomarker discovery in progressive supranuclear palsy from human cerebrospinal fluid using mass spectrometry-based proteomics

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder that is often misdiagnosed as Parkinsons Disease (PD) because of shared symptoms. PSP is characterized by the accumulation of tau protein in specific brain regions, which results in loss of balance, gaze impairment, and dementia. Diagnosing PSP is often challenging, and theres a significant demand for reliable biomarkers. However, existing biomarkers, including tau protein and neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF), show inconsistencies in distinguishing PSP from other neurodegenerative disorders. To overcome these limitations, we conducted a comprehensive proteome analysis for CSF samples from 40 PSP, 40 PD, and healthy controls (HC) using the tandem mass tag-based quantification method, identifying 3,653 unique proteins. Our statistical analysis identified 190, 152, and 247 differentially expressed proteins when comparing PSP vs. HC, PSP vs. PD, and PSP against both PD and HC, respectively. Gene set enrichment analysis and interactome analysis conducted with the differentially expressed proteins in PSP CSF indicated that most of them were implicated in cell adhesion, cholesterol metabolism, and glycan biosynthesis. Cell-type enrichment analysis revealed that neuronally-derived proteins were predominant among the differentially expressed proteins. Potential biomarker classification performance showed that ATP6AP2 (reduced in PSP) had the highest AUC (0.922), followed by NEFM, EFEMP2, LAMP2, CHST12, FAT2, B4GALT1, LCAT, CBLN3, FSTL5, ATP6AP1, and GGH. This is the first large-scale mass spectrometry-based proteome analysis to discover CSF PSP biomarkers differentiating from both controls and PD, thereby laying a foundation for further development and validation.

systems biology↗