Biology subjects

Schulz-Schaeffer, W.

Publications and source records attributed to Schulz-Schaeffer, W..

3 recordsLinked to original sources

bioRxiv2025

Single-cell Spatial Transcriptomics Reveals Disease-specificMicroenvironmental Niches in Neurodegeneration and COVID-19

Neurodegenerative diseases and infections can produce lasting effects on brain function, yet the spatial molecular mechanisms underlying these changes remain poorly understood. Here, we present high-resolution spatial transcriptomics of 40 postmortem brain samples from patients with Parkinsons disease, frontotemporal dementia, dementia with Lewy bodies, and severe COVID-19. Analyzing over 1.5 million spatially resolved cells across dorsolateral prefrontal cortex and anterior cingulate cortex revealed disease-specific transcriptional signatures with pronounced layer-and region-specificity. In Parkinsons disease, we identified stressed neurons creating distinctive microenvironmental gradients where metabolic and protein degradation pathways are elevated near stress epicenters, while regenerative processes increase with distance. COVID-19 brains displayed extensive peripheral immune cell infiltration, particularly in the subcortical white matter, accompanied by compromised blood-brain barrier and coordinated neuroinflammatory responses from microglia, astrocytes, and endothelial cells. Integration of miRNA sequencing with spatial transcriptomics uncovered layer-specific regulatory patterns, including neuroinflammation-associated miR-155. This atlas provides unprecedented insights into disease pathology and highlights the critical importance of spatial molecular context in understanding brain disorders. Key Messages[1] A high-resolution single-cell spatial transcriptomics atlas of the dorsolateral prefrontal cortex and anterior cingulate cortex across neurodegenerative conditions and severe COVID-19 [2] Region-and layer-specific transcriptional dysregulation across disease comparisons reveals disease-specific differential vulnerability [3] Metabolically stressed cells found selectively in the anterior cingulate cortex of Parkinsons disease patients but not in dementia with Lewy bodies, along with detailed characterization of their spatial microenvironment [4] Peripheral immune cell clusters identified in the white matter of the cerebral cortex of COVID-19 patients, with detailed characterization of their spatial microenvironment [5] Integration of bulk miRNA sequencing reveals cortical layer-specific miRNA regulatory patterns

neuroscience↗

bioRxiv2020

Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson disease

A key process of neurodegeneration in Parkinson disease (PD) is the transneuronal spreading of alpha-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of alpha-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of alpha-synuclein induced by intracerebral injection of alpha-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for alpha-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without alpha-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that alpha-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric alpha-synuclein species, which induce unusual microglial reactivity, play a key role in this process. Our findings uncover new features of alpha-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of prion-like spreading of that protein.

neuroscience↗

bioRxiv2020

Olfactory transmucosal SARS-CoV-2 invasion as port of Central Nervous System entry in COVID-19 patients

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease presenting with fever, cough, and often pneumonia. Moreover, thromboembolic events throughout the body including the central nervous system (CNS) have been described. Given first indication for viral RNA presence in the brain and cerebrospinal fluid and in light of neurological symptoms in a large majority of COVID-19 patients, SARS-CoV-2-penetrance of the CNS is likely. By precisely investigating and anatomically mapping oro- and pharyngeal regions and brains of 32 patients dying from COVID-19, we not only describe CNS infarction due to cerebral thromboembolism, but also demonstrate SARS-CoV-2 neurotropism. SARS-CoV-2 enters the nervous system via trespassing the neuro-mucosal interface in the olfactory mucosa by exploiting the close vicinity of olfactory mucosal and nervous tissue including delicate olfactory and sensitive nerve endings. Subsequently, SARS-CoV-2 follows defined neuroanatomical structures, penetrating defined neuroanatomical areas, including the primary respiratory and cardiovascular control center in the medulla oblongata.

neuroscience↗