Leukodystrophies due to astroyctic dysfunction

Abstract

Leukodystrophies are genetically determined disorders due to defects in any structural components of the brain white matter. This mini‐symposium presents a selection of leukodystrophies due to astrocytic dysfunction, the astrocytopathies. Examples are provided of astrocytopathies due to defects in astrocyte‐specific proteins and in which astrocytes play a major role in the pathophysiology. Knowledge on the disease mechanisms underlying these leukodystrophies also provides information how loss of physiologic functions and gain of detrimental functions in astrocytes leads to degeneration of the white matter.

Leukodystrophies are genetically determined disorders with selective involvement of the central nervous system white matter. Onset is at any age, from prenatal to elderly life. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is often progressive, but may also be static or even improving over time. Progressive leukodystrophies are often fatal, and no etiologic treatment is known. Recently, a tremendous increase occurred in the number of defined leukodystrophies also due to a diagnostic approach combining next generation sequencing and magnetic resonance imaging pattern recognition. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin‐ or oligodendrocyte‐specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels.

This issue of Brain Pathology presents a selection of leukodystrophies due to astrocytic dysfunction, the astrocytopathies. Astrocytes are central in maintaining brain health and function. In the white matter, they play roles in myelin maintenance, trophic support of axons, regulation of synaptic transmission, neurotransmitter production and recycling, blood‐brain barrier integrity and ion‐water homeostasis. Astrocytes are also central in responses to injury. Astrogliosis is a universal reaction to damage with beneficial and detrimental aspects. Upon damage, changes in gene expression, proliferation, morphology and function of astrocytes occur, tailored to context, insult type and severity. Astrocytes also orchestrate responses of surrounding cells also by secreting factors or altering extracellular matrix composition.

The disease mechanisms underlying astrocytopathies are a combination of loss of normal physiologic function (Figure 1) and gain of detrimental function. In this way, astrocytic pathology contributes to or even drives the degeneration of the white matter. This may occur in a cell‐autonomous and/or non‐cell‐autonomous way.

Figure 1.

Essential astrocytic functions that are lost in leukodystrophies.

Min and van der Knaap 2 review astrocytic leukodystrophies due to defects in ion‐water homeostasis. In the white matter, electrical activity of myelinated axons is caused by movement of ions inside and out of the cell accompanied by displacement of osmotically driven water. Since edema causes brain damage and can even be fatal, movement of ions and water has to be tightly regulated. Being equipped with specific ion and water channels, pumps and carriers, astrocytes play a crucial role in this process. Genetic defects are astrocytic proteins involved in ion‐water homeostasis lead to intra‐myelinic edema, which is the pathological hallmark of these leukodystrophies. The review integrates the current knowledge on ion‐water homeostasis also at the light of the information derived from the different diseases. The authors discuss how some defects in ion‐water homeostasis are reversible, implying that a thorough mechanistic understanding of how glial cells shape ion and water movement in the brain is also crucial for therapeutic purposes.

Sosunov and colleagues 4 review the current knowledge on Alexander Disease, a degenerative disorder caused by mutations in GFAP that encodes the major intermediate filament of astrocytes. GFAP is exclusively expressed by astrocytes, making Alexander disease an astrocytopathy. Alexander disease astrocytes impact on white matter integrity via cell‐autonomous and non‐cell‐autonomous mechanisms. They appear to lose the ability to support myelination and myelin maintenance, and acquire pathologic functions, including changes in morphology and activation of cell stress and inflammatory pathways. Besides on oligodendrocytes and microglia, Alexander disease astrocytes also impact on neurons causing cell loss in different neuronal populations. The authors underlie how knowledge of the disease mechanisms causing Alexander disease also sheds light on how astrocytes interact with other brain cells and how the process of astrogliosis that accompanies many neurological disorders can damage the function and survival of other cells.

Sase et al 3 review the disease mechanisms leading to Aicardi–Goutières syndrome, a genetically heterogeneous, early‐onset autoimmune disorder. Aicardi–Goutières syndrome is a type I interferonopathy characterized by overproduction of the cytokine interferon‐α and its downstream effectors. Astrocytes are one of the major source of interferon‐α in the brain, making them conceivable key players in the neuroinflammatory pathology typical of this disease. The review discusses known molecular and cellular pathways for Aicardi–Goutières syndrome mutations and how these stimulate interferon‐α signaling. The authors also discuss how compromised astrocytic function could contribute to neurodegeneration, addressing how astrocytes might play a central role in the phenotypic presentations of the disease through cell‐autonomous and non‐cell‐autonomous mechanisms. Understanding the contribution of astrocytes will pave the way to understand interferonopathies and develop targeted astrocyte‐specific therapeutic treatments for these diseases.

Bugiani and coworkers 1 review the white matter degenerative disease Vanishing white matter. Vanishing white matter is due to defects in the translation initiation factor eIF2B. Although eIF2B is a housekeeping factor, Vanishing white matter is mostly a leukodystrophy. Astrocytes play a central role in the disease, in both cell‐autonomous and non‐cell‐autonomous ways. They lose their normal function of sustaining white matter integrity and hamper the ability of oligodendrocyte progenitors to mature into myelin‐forming cells. Vanishing white matter astrocytes also display an alternative splicing deregulation of the intermediate filament GFAP, and are unable to proper react upon injury and perform a normal cross‐talk with inflammatory cells. Knowledge on how astrocytes are central in driving Vanishing white matter neuropathology is crucial also in view of the development of possible treatment strategies.

All in all, the mini symposium presented in this issue of Brain Pathology offers an overview on how astrocytes drive degeneration of the white matter through different disease mechanisms. The attentive reader will notice that some of these disease mechanisms are actually shared by different conditions. Alexander disease and Vanishing white matter, for example, most conceivably share some of the effects of an aberrant cytoskeletal intermediate filament composition, and its possible consequences on the process of reactive gliosis. They also share one possible disease mechanism, by which astrocytes hamper maturation of oligodendrocyte progenitors that is overproduction of the extracellular matrix component hyaluronan. Some mechanisms diverge completely amongst diseases, nonetheless leading to white matter degeneration. Neuroinflammation is triggered in Alexander disease and Aicardi–Goutières syndrome, but is typically meager in Vanishing white matter. Although still far from being complete, knowledge on the pathophysiology of the leukodystrophies here presented sheds light on how astrocytes biologically contribute to white matter integrity and function, and how loss of physiologic functions and gain of pathologic functions leads to white matter degeneration. This information is indispensable to develop targeted astrocyte‐specific therapeutic treatments for these diseases.