Dickson, Dennis W.

ABSTRACT Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a devastating, degenerative neurological disorder. It is inherited as an autosomal recessive trait caused by loss‐of‐function mutations in the galactocerebrosidase (GALC) gene. Previously, we have shown that peripheral injection of recombinant GALC, administered every other day, results in a substantial improvement in early clinical phenotype in the twitcher mouse model of GLD. While we did detect active enzyme in the brain following peripheral administration, most of the administered enzyme was localized to the periphery. Given the substantial central nervous system (CNS) involvement in this disease, we were interested in determining whether or not a single‐dose administration of the recombinant enzyme directly to the CNS, which could potentially be achieved clinically, would result in any substantial improvement. Following intracerebroventricu‐lar (icv) administration of GALC we noted a significant, 16.5%, reduction in the GALC substrate psychosine, the abnormal accumulation of which is believed to play a pivotal role in the CNS pathology observed in this disease. Moreover, recombinant GALC was found not only in periventricular regions but also at sites distant to the injection such as the cerebral cortex and cerebellum. Most importantly, animals receiving a single icv dose of the enzyme at postnatal day 20 survived up to 51 days, which compares favorably to the control twitcher animals, which normally only live to postnatal day 40/42. These results indicate that even a single icv administration of the recombinant enzyme can have significant clinical impact and suggests that other lysosomal storage disorders with significant CNS involvement may similarly benefit.—Lee, W.C., Tsoi, Y.K., Troendle, F.J., DeLucia, M.W., Ahmed, Z., Dicky, C.A., Dickson, D.W., Eckman, C.B. Single dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy. FASEB J. 21, 2520–2527 (2007)

This study identifies the actin-binding protein, coronin-1a, as a novel and effective immunohistochemical marker for microglia in both cell cultures and in formaldehyde-fixed, paraffin-embedded tissue. Antibodies to coronin-1a effectively immunostained microglia in human, monkey, horse, rat, and mouse tissues, even in tissues stored for long periods of time. The identity of coronin-1a-immunoreactive cells as microglia was confirmed using double immunolabeling with cell type-specific markers as well as by morphological features and the distribution of immunoreactive cells. These properties are shared by another actin-binding protein, IBA-1. Unlike IBA-1, coronin-1a immunoreactivity was also detected in lymphocytes and certain other hematopoietic cells. The results indicate that both coronin-1a and IBA-1 are robust markers for microglia that can be used in routinely processed tissue of humans and animals. Because both coronin-1a and IBA-1 are actin-binding proteins that play a role in rearrangement of the membrane cytoskeleton, it suggests that these proteins are critical to dynamic properties of microglia.