Martín-de-Saavedra MD, Dos Santos M, Culotta L, Varea O, Spielman BP, Parnell E, Forrest MP, Gao R, Yoon S, McCoig E, Jalloul HA, Myczek K, Khalatyan N, Hall EA, Turk LS, Sanz-Clemente A, Comoletti D, Lichtenthaler SF, Burgdorf JS, Barbolina MV, Savas JN, Penzes P.
Neuron, 2022.
Scientists demonstrate that a shed protein present in cerebrospinal fluid may play a role in neurological disease.
Ectodomain shedding (ES) is a process by which membrane-anchored cellular proteins break down and are released into the extracellular space, or ectodomain. Although ES is known to play a role in the development and physiology of the central nervous system and recent research has shown that soluble shed ectodomains may be linked to neurological disease, this relationship is not well understood.
In this study, researchers used a multiplatform approach to show that the neuronal sheddome is detectable in cerebrospinal fluid (CSF) and is enriched in neurodevelopmental risk factors. The scientists also demonstrated the presence in the CSF of a specific cell-adhesion molecule called contactin-associated protein-like 2 (CNTNAP2), which has known links to epilepsy, autism spectrum disorder, and intellectual disability. In other notable findings, the CNTNAP2 ectodomain (CNTNAP2-ecto) was found to modulate calcium homeostasis within neurons and regulate neural networks via the plasma membrane Ca2+ ATPase (PMCA) extrusion pumps.
To noninvasively examine neural network activity in primary cortical neurons label-free and in real time, the scientists used Axion’s multielectrode array (MEA) platform. Results showed that neurons treated with CNTNAP2-ecto displayed reduced network activity and synchrony in a PMCA2-dependent manner. Taken together with other results, the findings suggest that the sheddome may play an important role in neurological disease and further research is needed to discover its underlying mechanisms.
