Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

Abstract

Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a lysosomal storage disorder causing extensive demyelination in the central and peripheral nervous systems. GLD is caused by loss-of-function mutations in the lysosomal hydrolase, galactosylceramidase (GALC), which catabolizes the myelin sphingolipid galactosylceramide. The pathophysiology of GLD is complex and reflects the expression of GALC in a number of glial and neural cell types in both the central and peripheral nervous systems (CNS and PNS), as well as leukocytes and kidney in the periphery. Over the years, GLD has garnered a wide range of scientific and medical interests, especially as a model system to study gene therapy and novel preclinical therapeutic approaches to treat the spontaneous murine model for GLD. Here, we review recent findings in the field of Krabbe disease, with particular emphasis on novel aspects of GALC physiology, GLD pathophysiology, and therapeutic strategies.

Keywords: Krabbe disease; demyelination; leukodystrophy; neurodegeneration.

FIGURE 1

Galactosphingolipid biology in myelinating oligodendrocyte. The myelin sheath is a compact layer of lipid-rich membranes produced by oligodendrocytes in the central nervous system and by Schwann cells in the peripheral nervous system. Galactosylceramide (GalCer), a glycosphingolipid synthesized by ceramide synthase (CERS2) and ceramide galactosyl transferase (CGT), is a major component of myelin, present in the extracellular side of the membrane (so-called intraperiod line), see inset. GalCer can be further processed into sulfatides by addition of a sulfate group (red dots) by cerebroside sulfotransferase (CST). GalCer is catabolized into galactose (blue hexagons) and ceramide by galactosylceramidase and saposin A in the lysosome. Deficiency of these enzymes cause globoid cell leukodystrophy. CERS2, Ceramide synthase 2; CGT, ceramide galactosyl transferase; CST, cerebroside sulfotransferase; MBP, myelin basic protein; PLP, proteolipid protein

FIGURE 2

Cell-specific pathophysiology in the CNS of globoid cell leukodystrophy. “GALC +” area depicts cells that express galactosylceramidase enzyme and are physiologically normal. “GALC Null” area contains cells that lack galactosylceramidase enzyme and represent globoid cell leukodystrophy (GLD). GALC Null oligodendrocytes produce psychosine from GalCer via acid ceramidase, undergo diffuse loss of myelin, and contribute to secondary axonal degeneration. Psychosine in neurons causes axonal degeneration. Microglia and globoid cells are unable to digest myelin (GalCer) efficiently, accumulate cytosolic crystals and become proinflammatory, further contributing to axonal degeneration and compromising remyelination. Astrocytes become activated, presumably in response to the surrounding pathology

FIGURE 3

Demyelination, axonal degeneration and globoid cells in the nervous system of GLD-Krabbe patients. (a) Luxol-Fast-Blue, periodic acid schiff (PAS) staining of the cerebellar white matter from a GLD patient shows profound demyelination (absence of blue-stained myelin), neurodegeneration (low density of purple stained axons, arrows) and Globoid cells filled with PAS positive glycolipids storage (arrowhead). (b) Epon semithin sections of brachial plexus nerve from a globoid Leukodystrophy patient show very low density of myelinated fibers, myelinated fibers with onion bulbs (arrowhead) and many demyelinated fibers (double arrowheads), all indicative of chronic demyelination. Fiber density is also low, suggestive of chronic axonal degeneration. A globoid cell macrophage is indicated with an asterisk. Tissue (a) and image (b) courtesy of Dr. Julia Kofler and the NDRD brain and tissue bank at the University of Pittsburgh and Krabbe Partners for Research