Aberrant microglia function as drivers of neuroaxonal degeneration in diseases of the white matter

Aberrant microglia activation is a common hallmark of white matter diseases. Those include acquired diseases like multiple sclerosis (MS) as well as inherited X-linked cerebral adrenoleukodystrophy (CALD), and adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). Furthermore, in particular ALSP and CALD, but also MS (in chronic inactive lesions) are characterized by microglia death and limited repopulation. Efficiency of hematopoetic stem cell transplantation assumed to replace endogenous microglia by donor derived microglia like cells further underscores the pathogenic relevance of myeloid cell dysfunction in ALSP and CALD.
Though the disease-initiating mechanisms are distinct (adaptive and innate inflammatory, genetic-metabolic and genetic loss of microglia), these diseases have in common a substantial axonal pathology, reflected by conspicuous axonal spheroids, indicating axonal transport disturbance.

In this project, we will dissect the common and distinct microglia gene expression patterns related to neuronal and axonal damage in the different diseases by spatially resolved transcriptomic analyses of human CNS autopsy tissue and validate them in experimental models. We will assess if patient-derived microglia-like cells (MLCs) or human iPSC-derived microglia induce neuroaxonal pathology if transplanted in humanized mice.
Finally, we will assess microglia and MLC activation and function in vivo in patients with CALD and ALSP and correlate it to neuroaxonal damage as measured by high resolution functional microstructure MR imaging and inferred from serum and cerebrospinal fluid biomarkers.