Brain-Specific Aminopeptidase: From Enkephalinase to Protector Against Neurodegeneration

Abstract

The major breakthrough discovery of enkephalins as endogenous opiates led our attempts to determine their inactivation mechanisms. Because the NH2-terminal tyrosine is absolutely necessary for the neuropeptides to exert analgesic effects, and aminopeptidase activities are extraordinarily high in the brain, a specific "amino-enkephalinase" should exist. Several aminopeptidases were identified in the central nervous system during the search. In fact, our laboratory found two novel neuron-specific aminopeptidases: NAP and NAP-2. NAP is the only functionally active brain-specific enzyme known. Its synaptic location coupled with its limited substrate specificity could constitute a "functional" specificity and contribute to enkephalin-specific functions. In addition, NAP was found to be essential for neuron growth, differentiation, and death. Thus, aminopeptidases are likely important for mental health and neurological diseases. Recently, puromycin-sensitive aminopeptidase (PSA) was identified as a modifier of tau-induced neurodegeneration. Because the enzymatic similarity between PSA and NAP, we believe that the depletion of NAP in Alzheimer's disease (AD) brains plays a causal role in the development of AD pathology. Therefore, use of the puromycin-sensitive neuron-aminopeptidase NAP could provide neuroprotective mechanisms in AD and similar neurodegenerative diseases.

Suppression of Aβ toxicity by puromycin-sensitive aminopeptidase is independent of its proteolytic activity

“…In our model system, the Aβ peptide is secreted under the control of a signal peptide, which is cleaved off in the process [51]. The subcellular localization of PSA has not been conclusively demonstrated, although there are reports claiming it is secreted [52] these have been widely discounted in favor of an intracellular distribution (cytoplasmic [45], Golgi apparatus [53], and (peri)nuclear [54]) with a possibility of being membrane-bound [47,55,56]. A crucial goal of this study was to precisely locate PSA in our cell cultures and to determine whether a significant amount might cross membrane to come into contact with extracellular Aβ (or vice versa ).…”

FuncISH: learning a functional representation of neural ISH images

“…Npepps is an aminopeptidase that is active specifically in the brain (Hui, 2007), and the similarity between Synpo2 and Npepps is explained by processes related to protein processing, such as ubiquitination and protein proteolysis. At the same time, Rasa4 is a GTPase-activating protein that suppresses the Ras/mitogen-activated protein kinase pathway in response to Ca 2+ (Vigil et al , 2010), and the similarity between Synpo2 and Rasa4 is explained by high-level neural processes, such as axon guidance or synaptic transmission.…”

Plasma peptidases as prognostic biomarkers in patients with first-episode psychosis

“…It is also involved in the processing of bioactive peptides that are involved in regulation of mood and behavior (Maes et al, 1998). Hence, it is relevant to explore the involvement of aminopeptidase activity in synaptic neuropeptide degradation and control to elucidate the neurochemical mechanisms that are on the basis of mental health and neurological diseases, as is the case for aminopeptidase control of opioid peptides (Hui, 2007).…”