RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome

Abstract

Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. To date, investigations of neural anomalies in Down syndrome have focused on the central nervous system, although dysfunction of the peripheral nervous system is a common manifestation. The molecular and cellular bases underlying peripheral abnormalities have remained undefined. Here, we report the developmental loss of sympathetic innervation in human Down syndrome organs and in a mouse model. We show that excess regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of the calcineurin phosphatase that is triplicated in Down syndrome, impairs neurotrophic support of sympathetic neurons by inhibiting endocytosis of the nerve growth factor (NGF) receptor, TrkA. Genetically correcting RCAN1 levels in Down syndrome mice markedly improves NGF-dependent receptor trafficking, neuronal survival and innervation. These results uncover a critical link between calcineurin signalling, impaired neurotrophin trafficking and neurodevelopmental deficits in the peripheral nervous system in Down syndrome.

Phospho-Regulation of Soma-to-Axon Transcytosis of Neurotrophin Receptors

“…Sample sizes were similar to those reported in previous publications (Ascano et al, 2009; Bodmer et al, 2011; Patel et al, 2015). Data were collected randomly.…”

The neuronal and endocrine roles of RCAN1 in health and disease

“…Recent studies have confirmed that RCAN1 controls axon outgrowth by modulating growth cone actin dynamics by regulating the activity of multiple actin‐binding proteins . Additionally, elevated RCAN1 protein levels impair the innovation of sympathetic neurons by inhibiting receptor endocytosis and protein synthesis, further confirming the role of RCAN1 in the neurological disorders observed in DS individuals. In addition to its role in neuronal development and axon migration, studies have also implicated RCAN1 in the pathogenesis of other neurological disorders.…”

Neurotrophin signaling endosomes: biogenesis, regulation, and functions

“…Two recent studies provide insights into how altered neurotrophin endosomal signaling might contribute to the pathogenesis of neurodevelopmental disorders. Patel and colleagues highlighted a link between impaired neurotrophin trafficking and neurodevelopmental defects in the peripheral nervous system in Down syndrome [46]. One of the genes that is triplicated in Down syndrome is Regulator of Calcineurin1 ( RCAN1 ), an endogenous calcineurin inhibitor.…”

“…Since reducing RCAN1 gene dosage did not fully rescue sympathetic neuronal deficits in Down syndrome mice, it is likely that RCAN1 cooperates with other human chromosome 21 gene products such as amyloid precursor protein[47] and intersectin, a known endocytic regulator[48], to elicit sympathetic nervous system dysfunction in Down syndrome. The defects in retrograde NGF trafficking and developmental abnormalities in the sympathetic nervous system in Down syndrome mice are of interest because sympathetic innervation was also found to be diminished in peripheral organs from infants with Down syndrome [46]. Together, the findings suggest anatomical and cellular bases for the reported autonomic dysfunction in the disease including impaired neural regulation of heart rate and blood pressure.…”