Distribution of prosaposin‐like immunoreactivity in rat brain

Abstract

Prosaposin is the precursor for saposins A, B, C, and D, which are small lysosomal proteins required for the hydrolysis of sphingolipids by specific lysosomal hydrolases. With a monospecific anti-saposin C antibody, which cross-reacts with prosaposin but not with saposin A, B, or D, the present immunoblot experiments showed that the rat brain expresses an unprocessed approximately 72 kDa protein (possibly prosaposin) and little saposin C. Regional analysis demonstrated that prosaposin is abundant in the brainstem, hypothalamus, cerebellum, striatum, and hippocampus, and less abundant in the cerebral cortex. Consistent with this finding, prosaposin-like immunoreactive neurons and fibers as revealed by immunohistochemistry were observed frequently in subcortical regions. The medial septum, diagonal bands, basal nucleus of Meynert, ventral striatum, medial habenular nucleus, and motor nuclei of cranial nerve had significant numbers of immunoreactive neurons. There were also nerve fibers with prosaposin-like immunoreactivity in several projection fields of the above nuclei. Other brain areas that contained prosaposin-like immunoreactive neurons and/or processes were: several brain nuclei (nucleus caudate putamen, globus pallidus, substantia nigra, red nucleus) constituting the so-called extrapyramidal system, reticular thalamic nucleus, entopeduncular nucleus, mammillary nuclei, auditory relay nuclei, cerebellum, sensory cranial nerve nuclei, and the reticular formation. The distribution pattern of prosaposin is apparently different from that of other neuroactive substances so far examined, and thus prosaposin may be involved in novel central events.

Functional Organization of Saposin C

“…Importantly, the neurite outgrowth effects are cell-specific because NS20Y, a cholinergic neuroblastoma cell line, responded better than Neuro2A, a noncholinergic cell line (23). This is consistent with the localization of prosaposin, as opposed to the individual saposins, to cholinergic neurons in rat brain (37). These results imply that the prosaposin-mediated neurotrophic effects, via its saposin C segment, may be mainly in specific sets of neurons.…”

Identification of prosaposin as a neurotrophic factor.

“…Immunocytochemical studies using a prosaposinspecific antibody demonstrated high concentrations of prosaposin in human cortical neurons (unpublished data). A similar survey in rat brain demonstrated widespread prosaposin immunoreactivity in neurons (9). Total prosaposin deficiency in humans due to a point mutation in the start codon of the prosaposin gene (24) resulted in severe neurological deterioration evident at birth with prominent cortical hypomyelination and cerebral atrophy (25).…”

“…In addition to its role as a lysosomal precursor, prosaposin is presumed to have additional functions, since it exists as a secretory protein in human milk, cerebrospinal fluid, and seminal plasma (3)(4)(5); it is present in unprocessed form in high concentrations in human (6) and rat (7) brain; its mRNA is abundant in brain and dorsal root ganglia during embryonic development (8); it is present predominantly in neurons after immunostaining (9); and it occurs as an integral membrane component (10).…”

Shedding and uptake of gangliosides and glycosylphosphatidylinositol-anchored proteins

“…Prosaposin can also be found in many biological fluids such as seminal plasma, human milk, and cerebrospinal fluid (reviewed in [120]). Prosaposin is abundant in the brain where it is localized exclusively in certain neurons [121]. Its presence on the neuronal surface was first reported by Fu and colleagues in 1994 [122] and since then many functions have been attributed to the secreted form of prosaposin.…”