title: Neurolysosomal pathology in human prosaposin deficiency suggests essential neurotrophic function of prosaposin.
abstract: A neuropathologic study of three cases of prosaposin (pSap) deficiency (ages at death 27, 89 and 119 days), carried out in the standard autopsy tissues, revealed a neurolysosomal pathology different from that in the non-neuronal cells. Non-neuronal storage is represented by massive lysosomal accumulation of glycosphingolipids (glucosyl-, galactosyl-, lactosyl-, globotriaosylceramides, sulphatide, and ceramide). The lysosomes in the central and peripheral neurons were distended by pleomorphic non-lipid aggregates lacking specific staining and autofluorescence. Lipid storage was borderline in case 1, and at a low level in the other cases. Neurolysosomal storage was associated with massive ubiquitination, which was absent in the non-neuronal cells and which did not display any immunohistochemical aggresomal properties. Confocal microscopy and cross-correlation function analyses revealed a positive correlation between the ubiquitin signal and the late endosomal/lysosomal markers. We suppose that the neuropathology most probably reflects excessive influx of non-lipid material (either in bulk or as individual molecules) into the neurolysosomes. The cortical neurons appeared to be uniquely vulnerable to pSap deficiency. Whereas in case 1 they populated the cortex, in cases 2 and 3 they had been replaced by dense populations of both phagocytic microglia and astrocytes. We suggest that this massive neuronal loss reflects a cortical neuronal survival crisis precipitated by the lack of pSap. The results of our study may extend the knowledge of the neurotrophic function of pSap, which should be considered essential for the survival and maintenance of human cortical neurons.
authors.affiliation: Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University and General Teaching Hospital, Ke Karlovu 2, Prague 2, 12808, Czech Republic.
authors.forename: Jakub
authors.initials: J
authors.lastname: Sikora
authors.forename: Klaus
authors.initials: K
authors.lastname: Harzer
authors.forename: Milan
authors.initials: M
authors.lastname: Elleder
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001344:Autopsy; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology; D002648:Child; D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D016464:Lysosomal Storage Diseases / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure*; D049231:Saposins / Q000172:deficiency* / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015816:Cell Adhesion Molecules, Neuronal; D058851:GPI-Linked Proteins; D005904:Glial Fibrillary Acidic Protein; D006028:Glycosphingolipids; D049231:Saposins; D025801:Ubiquitin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C483345:PSAP protein, human; C095362:limbic system-associated membrane protein