BACE1 activity is significantly increased in the brains of Alzheimer's disease patients, potentially contributing to neurodegeneration. The voltage-gated sodium channel (Na(v)1) beta2-subunit (beta2), a type I membrane protein that covalently binds to Na(v)1 alpha-subunits, is a substrate for BACE1 and gamma-secretase. Here, we find that BACE1-gamma-secretase cleavages release the intracellular domain of beta2, which increases mRNA and protein levels of the pore-forming Na(v)1.1 alpha-subunit in neuroblastoma cells. Similarly, endogenous beta2 processing and Na(v)1.1 protein levels are elevated in brains of BACE1-transgenic mice and Alzheimer's disease patients with high BACE1 levels. However, Na(v)1.1 is retained inside the cells and cell surface expression of the Na(v)1 alpha-subunits and sodium current densities are markedly reduced in both neuroblastoma cells and adult hippocampal neurons from BACE1-transgenic mice. BACE1, by cleaving beta2, thus regulates Na(v)1 alpha-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity.

Spinal muscular atrophy (SMA), caused by the deletion of the SMN1 gene, is the leading genetic cause of infant mortality. SMN protein is present at high levels in both axons and growth cones, and loss of its function disrupts axonal extension and pathfinding. SMN is known to associate with the RNA-binding protein hnRNP-R, and together they are responsible for the transport and/or local translation of β-actin mRNA in the growth cones of motor neurons. However, the full complement of SMN-interacting proteins in neurons remains unknown. Here we used mass spectrometry to identify HuD as a novel neuronal SMN-interacting partner. HuD is a neuron-specific RNA-binding protein that interacts with mRNAs, including candidate plasticity-related gene 15 (cpg15). We show that SMN and HuD form a complex in spinal motor axons, and that both interact with cpg15 mRNA in neurons. CPG15 is highly expressed in the developing ventral spinal cord and can promote motor axon branching and neuromuscular synapse formation, suggesting a crucial role in the development of motor axons and neuromuscular junctions. Cpg15 mRNA previously has been shown to localize into axonal processes. Here we show that SMN deficiency reduces cpg15 mRNA levels in neurons, and, more importantly, cpg15 overexpression partially rescues the SMN-deficiency phenotype in zebrafish. Our results provide insight into the function of SMN protein in axons and also identify potential targets for the study of mechanisms that lead to the SMA pathology and related neuromuscular diseases.neuritin | embryonic lethal abnormal vision Drosophila-like 4 (ELAV-L4) | local protein synthesis S pinal muscular atrophy (SMA) is a devastating genetic disease leading to infant mortality, due mainly to the loss of α-motor neurons of the spinal cord and brainstem nuclei. SMA occurs due to depletion of a ubiquitously expressed protein, SMN, which in all cells regulates RNA biogenesis and splicing through its role in the assembly of small nuclear ribonucleoprotein (snRNP) complexes (1). Despite the well-characterized association of SMN with the snRNP complex in both the nucleus and cytoplasm of motor neurons, in the axons SMN associates with mobile ribonucleoprotein (RNP) particles that are free of the core snRNP complex proteins (2). Thus, it is hypothesized that SMN may function in the assembly of axonal RNPs to regulate axonal mRNA transport and/or local protein synthesis (3, 4). Deficits in mRNA transport and local mRNA translation are associated with such neurologic disorders as fragile X syndrome and tuberous sclerosis (5, 6). Therefore, the interaction of SMN complex with other RNPs and their associated mRNAs within the axon may be crucial to understanding the pathophysiology of SMA.At present, the only RNP known to bind SMN in the axons is hnRNP-R, which regulates β-actin mRNA localization in growth cones (4). In fact, dissociated motor neurons from a severe SMNdeficiency mouse model, Smn −/− ;SMN2tg, display defects in axonal growth and growth cone morphology and contain reduced level...