Studies

Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin ...

To study mechanisms of neurodegenerative diseases, neuronal cell lines are important model systems and are often differentiated into postmitotic neuron-like cells to resemble more closely primary neurons obtained from brains. One such cell line is the Lund Human Mesencephalic (LUHMES) cell line which can be differentiated into dopamine-like neurons and is frequently used to study mechanisms of Parkinson’s disease (PD) and neurotoxicity. Neuronal differentiation of LUHMES cells is commonly verified ...

Oligodendrocytes extend numerous cellular processes that wrap multiple times around axons to generate lipid-rich myelin sheaths. Myelin biogenesis requires an enormously productive biosynthetic machinery for generating and delivering these large amounts of newly synthesized lipids. Yet, a complete understanding of this process remains elusive. Utilizing volume electron microscopy, we demonstrate that the oligodendroglial endoplasmic reticulum (ER) is enriched in developing myelin, extending into ...

The metalloprotease ADAM10 is a drug target in Alzheimer's disease, where it cleaves the amyloid precursor protein (APP) and lowers amyloid-beta. Yet, ADAM10 has additional substrates, which may cause mechanism-based side effects upon therapeutic ADAM10 activation. However, they may also serve-in addition to APP-as biomarkers to monitor ADAM10 activity in patients and to develop APP-selective ADAM10 activators. Our study demonstrates that one such substrate is the neuronal cell adhesion protein ...

Age-related myelin damage induces inflammatory responses, yet its involvement in Alzheimer’s disease remains uncertain, despite age being a major risk factor. Using a mouse model of Alzheimer’s disease, we found that amyloidosis itself triggers age-related oligodendrocyte and myelin damage. Mechanistically, CD8+ T cells promote the progressive accumulation of abnormally interferon-activated microglia that display myelin-damaging activity. Thus, our data suggest that immune responses against ...

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of ...

Direct reprogramming based on genetic factors resembles a promising strategy to replace lost cells in degenerative diseases such as Parkinson's disease. For this, we developed a knock‐in mouse line carrying a dual dCas9 transactivator system (dCAM) allowing the conditional in vivo activation of endogenous genes. To enable a translational application, we additionally established an AAV‐based strategy carrying intein‐split‐dCas9 in combination with activators (AAV‐dCAS). Both approaches were ...