Functions of 'A disintegrin and metalloproteases (ADAMs)' in the mammalian nervous system

Abstract

'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.

Keywords: ADAM; Ectodomain shedding; Metalloprotease; Neural development; Neurological disease.

Fig. 1

Typical domain structure of ADAM proteins. The region within the catalytic region essential for active ADAMs is highlighted. Note that the EGF domain is not found in all ADAMs, e.g., in ADAM10

Fig. 2

Overview of ADAMs functions in the nervous system. ADAM proteins play diverse roles in the mammalian nervous system. Relevant ADAMs in the regulation of indicated physiological or pathological conditions are listed. Some functions have been well established either through in vivo studies or genetics. Other functions are more suggestive to date. For details, see the corresponding paragraph on each ADAM family member. The pictures were modified from https://smart.servier.com

Fig. 3

The function of inactive ADAM11, 22 and 23 in the nervous system. Presynaptic ADAM11 and ADAM23 regulate Kv1 channels. ADAM23 binds LGI1, bridging the synaptic cleft to ADAM22. Postsynaptic ADAM22 interacts extracellularly with LGI1 and intracellularly with PSD-95. This interaction is important for synapse maturation and regulates AMPA receptors (AMPAR)

Fig. 4

Key substrates and functions of ADAM10 in the nervous system. a ADAM10 (represented by black scissors) cleaves the Notch receptor at the Notch juxtamembrane region. Subsequently, the C-terminal fragment (CTF) of Notch is further processed by the protease γ-secretase, generating the Notch intracellular domain (NICD), which translocates to the nucleus and activates target gene expression relevant during neural development. b In the CNS (left), ADAM10 cleaves several cell adhesion molecules, e.g., EphrinA5, NCAM, NrCAM, and Nrp1, and thus regulates axon targeting and neurite growth. In the PNS (right), ADAM10 is the major protease to release the soluble DR6 ectodomain (sDR6), which in turn negatively regulates axonal myelination by Schwann cells (SCs). c ADAM10 regulates synapse formation and maintenance by cleaving several key synaptic proteins localized to both pre-synapse and post-synapse, e.g., N-cadherin, neuroligin-1 (NLGN1), and neurexin (NRXN). d ADAM10 cleaves APP within the Aβ sequence, which precludes the formation of pathological Aβ plaques in AD (left). ADAM10 plays a dual role in prion disease (right), as on one hand ADAM10 inhibits the transition of cellular prion protein (PrP^c) to pathological prion protein (PrP^sc), but on the other hand promotes the spreading of PrP^sc