Biology subjects

Pritzkow, S.

Publications and source records attributed to Pritzkow, S..

3 recordsLinked to original sources

bioRxiv2026

Seed Amplification Assay-Based Detection of Alpha-Synuclein Aggregates Outperforms Immunohistochemical Analysis in the Intestinal Mucosal Biopsies of Parkinson's Disease and Multiple System Atrophy Participants

Objective: To determine whether an -synuclein (-Syn) seed amplification assay (SAA) detects seeding-competent aggregates in endoscopic mucosal biopsies, differs by gastrointestinal region, registers pathology more frequently than immunohistochemistry (IHC), and associates with Parkinson disease (PD) diagnosis, disease duration or severity. Design: This cross-sectional, proof-of-concept diagnostic accuracy study analyzed duodenum, ileum, and sigmoid biopsies from PD participants, age- and sex-matched healthy controls (HC), plus exploratory multiple system atrophy (MSA) subtypes [parkinsonian (MSA-P) and cerebellar (MSA-C)]. Ileal and sigmoid PD and HC biopsies were assessed using proteinase K-resistant phospho-Ser129 IHC. SAA positivity was evaluated against clinical and biological measures. Results: In PD, SAA detected seeding competent -Syn aggregates with high observed specificity (97.5-100%) and region-dependent sensitivity (18/37, 48.65% in ileum and 36/56, 64.29% in sigmoid). Sigmoid SAA positivity increased significantly with PD disease duration (40.00% at <5 years, 73.33% at 5-10 years, and 93.75% at >10 years), independent of motor severity, whereas ileal positivity remained stable across disease stages. In 37 paired sigmoid biopsies, SAA detected -Syn aggregates 2.8-fold more frequently than IHC. Sigmoid seeding activity was detected in all five MSA-P, but not in two MSA-C. IHC did not detect aggregates in any MSA. Conclusions: In PD, -Syn SAA detected seeding-competent -Syn aggregates in endoscopic mucosal biopsies with high observed specificity, moderate sensitivity, and approximately 2.8-fold higher detection rate than IHC in sigmoid. Positive SAA in MSA patients supports GI involvement across synucleinopathies. SAA detection in PD differed by intestinal region and disease duration, supporting further validation of intestinal SAA as a PD biomarker.

neuroscience↗

bioRxiv2025

Aggregation-prone alpha-synuclein proteoforms and dysregulated molecular signatures in the vermiform appendix of synucleinopathy patients

Synucleinopathies, including Parkinsons disease, are neurodegenerative diseases characterized by intracellular inclusions containing the amyloidogenic protein alpha-synuclein. While classically considered to be brain disorders, increasing evidence suggests involvement of the gut, with alpha-synuclein aggregates potentially propagating to the brain via the vagus nerve. Evidence also suggests that the vermiform appendix is particularly susceptible to alpha-synuclein aggregation, and appendectomy impacts the onset of Parkinsons disease. However, the mechanisms underlying the aggregation of alpha-synuclein in the vermiform appendix remains poorly understood. To explore this, we assessed aggregation properties in postmortem appendix tissues from healthy controls and synucleinopathy patients using the alpha-synuclein seed amplification assay (alpha-synuclein-SAA) and performed total RNA sequencing alongside differential bisulfite-hybridization-based DNA methylation analysis in the same tissues to investigate the molecular underpinnings. Moreover, we determined alpha-synuclein cleavage patterns by cataloging soluble alpha-synuclein proteoforms from postmortem substantia nigra and post-surgical appendix tissues using top-down mass spectrometry (TD-MS). Alpha-synuclein-SAA was positive in appendix samples for 68.75% of synucleinopathy patients and 6.6% of controls. Genomic profiling revealed dysregulated expression of genes linked to protein folding/degradation, immune/inflammatory responses, and ciliary dynamics in synucleinopathy appendix tissues. TD-MS identified 65 distinct alpha-synuclein proteoforms in the substantia nigra and appendix, with 9 unique to the appendix. Further, in silico modeling revealed higher aggregation propensity of alpha-synuclein proteoforms in the appendix versus substantia nigra. Together, our findings suggest that a tissue environment of alpha-synuclein dysproteostasis in the appendix has the potential to contribute to the development of synucleinopathies. One Sentence SummaryAppendixes from synucleinopathy patients show altered gene expression, unique -syn proteoforms, and higher aggregation propensity than substantia nigra.

neuroscience↗

bioRxiv2019

Bacterial DNA promotes Tau aggregation

A hallmark feature of Alzheimers disease (AD) and other tauopathies is the misfolding, aggregation and cerebral accumulation of tau deposits. Compelling evidence indicates that misfolded tau aggregates are neurotoxic, producing synaptic loss and neuronal damage. Misfolded tau aggregates are able to spread the pathology from cell-to-cell by a prion like seeding mechanism. The factors implicated in the initiation and progression of tau misfolding and aggregation are largely unclear. In this study, we evaluated the effect of DNA extracted from diverse prokaryotic and eukaryotic cells in tau misfolding and aggregation. Our results show that DNA from various, unrelated gram-positive and gram-negative bacteria results in a more pronounced tau misfolding compared to eukaryotic DNA. Interestingly, a higher effect in promoting tau aggregation was observed for DNA extracted from certain bacterial species previously detected in the brain, CSF or oral cavity of patients with AD. Our findings indicate that microbial DNA may play a previously overlooked role in the propagation of tau protein misfolding and AD pathogenesis, providing a new conceptual framework that positions the compromised blood-brain and intestinal barriers as important sources of microbial DNA in the CNS, opening novel opportunities for therapeutic interventions.

microbiology↗