Biology subjects

Skotte, N. H.

Publications and source records attributed to Skotte, N. H..

4 recordsLinked to original sources

bioRxiv2025

Distinct and Combined Interferon-α/β-receptor-1 Loss in Neurons and Astrocytes Disrupt Brain Energy Metabolism and Drive Parkinsonian Dementia

Dysregulated interferon-alpha/beta-receptor 1 (IFNAR1) signaling was recently identified to contribute to the development of sporadic Parkinsons Disease (PD) into PD with Dementia (PDD). The molecular, cellular, and phenotypic impacts of brain IFNAR1 loss in aging have not been explored in vivo, which may reveal novel disease mechanisms and therapeutic targets. Here it is shown that baseline IFNAR1 expression varies in the major brain cell types, including neurons and astrocytes, and is differentially affected in PD and Lewy Body Dementia patients compared to unaffected controls. Neuron- and astrocyte-specific transcriptomic and proteomic alterations in Ifnar1-/- mice implicate mitochondrial defects and synergistic dysfunctional neurotransmission upon IFNAR1 loss, leading to glucose hypermetabolism measured by functional metabolic analysis. Consequently, Ifnar1-/- mice exhibited PDD-like pathogenesis, including dopaminergic cell loss in the substantia nigra, cortical neurodegeneration, Lewy-body-like inclusions, neuroinflammation, and progressive PDD-like behavior deficits. Brain cell-specific IFNAR1 loss examined in vivo revealed delayed but distinct development of PDD-like phenotypes, where neuropathology, motor, and cognitive behavior deficits were specifically recapitulated only in mice lacking neuronal IFNAR1, and behavior resembling neuropsychiatric abnormalities recapitulated only in mice lacking astrocytic IFNAR1. This work supports a crucial role of IFNAR1 in brain homeostasis and emphasizes a need for understanding neurodegenerative pathophysiology in cell-specific contexts. HighlightsO_LIIFNAR1 and related type-I IFN genes are differentially expressed among major brain cell types in Parkinsons Disease, Lewy Body Dementia, and unaffected controls C_LIO_LIEarly molecular alterations in Ifnar1-/- mice show lack of immunomodulation contributing to neuroinflammation, mitochondrial defects, and dysregulated energy metabolism C_LIO_LIIfnar1-/- mice develop a progressive Parkinsonian-like disease phenotype, including dopaminergic cell loss in substantia nigra, cortical neurodegeneration, phosphorylated (p)alpha-synuclein+ and pTau+ Lewy-body-like inclusions, neuroinflammation, and progressive motor, cognitive, and neuropsychiatric disturbance-like behavior deficits C_LIO_LINeuropathologies, motor, and cognitive deficits are recapitulated in mice lacking neuronal IFNAR1 (Syn1Cre;Ifnar1fl/fl) whereas neuropsychiatric abnormalities are recapitulated in mice lacking astrocytic IFNAR1 (GFAPCre;Ifnar1fl/fl) C_LI

neuroscience↗

bioRxiv2025

Vascular dysfunction in Huntington's disease is located at the blood-CSF barrier and is rescued by sphingosine-1-phosphate receptor agonist

Brain vascular barriers are dysfunctional in many neurological disorders, including Huntingtons disease (HD), but which vessels are affected and how remains unclear. Using in vivo two-photon microscopy in R6/2 HD-model mice, we reveal a striking divergence in barrier dysfunction. Surface vessels of the blood-cerebrospinal fluid barrier (BCSFB) drive pathology by paracellular leakage, while the blood-brain barrier (BBB) of parenchymal arterioles and capillaries exhibited increased vesicular transport and adsorptive-mediated transcytosis (AMT), with arterioles being the most susceptible segment. The pathology of both barriers was congruent with astrocyte activation localized to affected vessels in R6/2 mice, as well as in post-mortem HD human brains. Sphingosine-1-phosphate receptor 1 (S1PR1) agonist treatment rescued BCSFB leakage but only partially restored BBB function, selectively reducing AMT in arterioles, with no effect in capillaries and venules. These findings redefine HD vascular pathology, demonstrating heterogeneous, vessel-type-specific barrier failure beyond generalized "disruption," uncovering mechanistic vulnerabilities and the therapeutic potential of S1PR1 modulation.

neuroscience↗

bioRxiv2019

Integrative analysis identifies key molecular signatures underlying neurodevelopmental deficits in Fragile X Syndrome

Fragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing of FMR1 and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenic FMR1 knockout (FMR1KO) human embryonic stem cells (hESCs). Integrative analysis of the transcriptomic and proteomic profiles of hESC-derived FMRP-deficient neurons revealed several dysregulated pathways important for brain development including processes related to axon development, neurotransmission, and the cell cycle. We functionally validated alterations in a number of these pathways, showing abnormal neural rosette formation and increased neural progenitor cell proliferation in FMR1KO cells. We further demonstrated neurite outgrowth and branching deficits along with impaired electrophysiological network activity in FMRP-deficient neurons. Using isogenic FMR1KO hESC-derived neurons, we reveal key molecular signatures and neurodevelopmental abnormalities arising from loss of FMRP. We anticipate that the FMR1KO hESCs and the neuronal transcriptome and proteome datasets will provide a platform to delineate the pathophysiology of FXS in human neural cells.

neuroscience↗

bioRxiv2017

Feeding Schedule And Proteolysis Regulate Autophagic Clearance Of Mutant Huntingtin

The expression of mutant huntingtin (mHTT) causes Huntington disease (HD), and lowering its levels is therefore an attractive therapeutic strategy. Here we show that scheduled feeding significantly decreases mHTT protein levels through enhanced autophagy in the CNS of an HD mouse model, while short term fasting is sufficient to observe similar effects in peripheral tissue. Furthermore, preventing proteolysis at the caspase-6 cleavage site D586 (C6R) makes mHTT a better substrate for autophagy, additionally increasing its clearance. Mice expressing mutant C6R also exhibit increased autophagy at baseline compared to an HD model with cleavable mHTT, suggesting that the native function of HTT in promoting autophagy is disrupted upon cleavage and re-established by prevention of cleavage by caspase-6. In HD patients, mHTT clearance and autophagy may therefore become increasingly impaired as a function of age and disease stage by gradually increased activity of mHTT-processing enzymes.

neuroscience↗