Reelin proteolysis affects signaling related to normal synapse function and neurodegeneration

Reelin is a neurodevelopmental protein important in adult synaptic plasticity and learning and memory. Recent evidence points to the importance for Reelin proteolysis in normal signaling and in cognitive function. Support for the dysfunction of Reelin proteolysis in neurodegeneration and cognitive dysfunction comes from postmortem analysis of Alzheimer’s diseases (AD) tissues including cerebral spinal fluid (CSF), showing that levels of Reelin fragments are altered in AD compared to control. Potential key proteases involved in Reelin proteolysis have recently been defined, identifying processes that could be altered in neurodegeneration. Introduction of full-length Reelin and its proteolytic fragments into several mouse models of neurodegeneration and neuropsychiatric disorders quickly promote learning and memory. These findings support a role for Reelin in learning and memory and suggest further understanding of these processes are important to harness the potential of this pathway in treating cognitive symptoms in neuropsychiatric and neurodegenerative diseases. Neurodegenerative diseases are characterized by the progressive loss of synapses and neurons, accounting for cognitive deterioration. One molecular pathway that is well characterized in playing a role in adult synaptic plasticity and learning and memory is the Reelin signaling pathway (Weeber et al., 2002; Chen et al., 2005; Qiu et al., 2006a,b; Qiu and Weeber, 2007; Rogers et al., 2011). Reelin is also involved in a number of neurodegenerative and neuropsychiatric disorders presenting with cognitive deficits, including schizophrenia (Guidotti et al., 2000; Chen et al., 2002; Fatemi, 2005; Torrey et al., 2005), bipolar disorder (Fatemi et al., 2000; Torrey et al., 2005), depression (Knable et al., 2004; Lussier et al., 2009, 2011, 2013a,b; Fenton et al., 2015), epilepsy (Fournier et al., 2010; Haas and Frotscher, 2010; Dutta et al., 2011) and autism (Fatemi et al., 2005). Furthermore, Reelin signal transduction pathways appear to be particularly vulnerable in Alzheimer’s disease (AD), potentially contributing to its pathogenesis (Hoe et al., 2006; Hoareau et al., 2008). Thus, a better understanding of Reelin signaling could be useful in developing therapies against synaptic and neuronal loss in a number of conditions.