Reelin (F8Z8Y) Rabbit Monoclonal Antibody #65212

Reelin, a secreted glycoprotein, plays critical roles in neuronal development, health, and disease. Structurally, reelin consists of an N-terminal F-spondin-like domain, eight reelin repeat (RR) domains (RR1-8), and a C-terminal domain predominantly made up of basic amino acids. Full-length reelin contains two main cleavage sites, an N-terminal cleavage site within RR3, and a C-terminal cleavage site between RR6 and RR7. Cleavage is driven by several proteases, including tissue plasminogen activator (tPA), meprin α and β, and members of the A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) family. Five fragments can be produced by these cleavage events, each with varying impacts on reelin migration, function, and downstream signaling. RR domains 3-6, which are retained in three out of five of these fragments, are particularly important for binding two canonical receptors of Reelin, apolipoprotein E receptor 2 (ApoER2, also known as LRP8) and very low-density lipoprotein receptor (VLDLR). Upon binding, these receptors cluster, which in turn drives the clustering and tyrosine phosphorylation of the intracellular adaptor protein Disabled 1 (Dab1) by Src family kinases (SFK), Src and Fyn. This leads to downstream signaling cascades that regulate various functions, including neuronal migration, dendritic growth and maturation, synaptogenesis, synaptic plasticity, cell adhesion, and proliferation (1-3). Loss or dysfunction of reelin signaling is associated with neurodevelopmental disorders, including lissencephaly and autism spectrum disorder (ASD), as well as psychiatric disorders, including schizophrenia, bipolar disorder, and depression. Reelin dysfunction is also implicated in the etiology of neurodegenerative disorders, including ataxias, traumatic brain injury (TBI), and Alzheimer’s disease (AD) (1,4). The two pathological hallmarks of AD are extracellular accumulation of amyloid beta (Aβ) plaques, driven by amyloidogenic processing of the Aβ precursor protein (APP), and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Studies suggest that reelin and other components of this signaling pathway can act to both reduce amyloidogenic processing of APP and inhibit GSK-3β, a kinase heavily involved in the hyperphosphorylation of tau (3-5). Further supporting reelin as a potential therapeutic target for AD is a study showing that a gain-of-function variant (H3447R) of reelin, termed RELN-COLBOS, provided cognitive resilience in a male carrying the presenilin 1 mutation (PSEN1-E280A), an autosomal dominant AD mutation (6).