Nogo-A controls structural plasticity at dendritic spines by rapidly modulating actin dynamics.

Nogo-A and its receptors have been shown to control synaptic plasticity, including negatively regulating long-term potentiation (LTP) in the cortex and hippocampus at a fast time scale and restraining experience-dependent turnover of dendritic spines over days. However, the molecular mechanisms and the precise time course mediating these actions of Nogo-A are largely unexplored. Here we show that Nogo-A signaling in the adult nervous system rapidly modulates the spine actin cytoskeleton within minutes to control structural plasticity at dendritic spines of CA3 pyramidal neurons. Indeed, acute Nogo-A loss-of-function transiently increases F-actin stability and results in an increase in dendritic spine density and length. In addition, Nogo-A acutely restricts AMPAR insertion and mEPSC amplitude at hippocampal synaptic sites. These data indicate a crucial function of Nogo-A in modulating the very tight balance between plasticity and stability of the neuronal circuitry underlying learning processes and the ability to store long-term information in the mature CNS. © 2016 Wiley Periodicals, Inc.

NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale.

Whereas the role of NogoA in limiting axonal fiber growth and regeneration following an injury of the mammalian central nervous system (CNS) is well known, its physiological functions in the mature uninjured CNS are less well characterized. NogoA is mainly expressed by oligodendrocytes, but also by subpopulations of neurons, in particular in plastic regions of the CNS, e.g., in the hippocampus where it is found at synaptic sites. We analyzed synaptic transmission as well as long-term synaptic plasticity (long-term potentiation, LTP) in the presence of function blocking anti-NogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO mice. Whereas baseline synaptic transmission, short-term plasticity and long-term depression were not affected by either approach, long-term potentiation was significantly increased following NogoA or NgR1 neutralization. Synaptic potentiation thus seems to be restricted by NogoA. Surprisingly, synaptic weakening was not affected by interfering with NogoA signaling. Mechanistically of interest is the observation that by blockade of the GABA(A) receptors normal synaptic strengthening reoccurred in the absence of NogoA signaling. The present results show a unique role of NogoA expressed in the adult hippocampus in restricting physiological synaptic plasticity on a very fast time scale. NogoA could thus serve as an important negative regulator of functional and structural plasticity in mature neuronal networks.

Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence.

Iron deprivation activates mitophagy and extends lifespan in nematodes. In patients suffering from Parkinson's disease (PD), PINK1-PRKN mutations via deficient mitophagy trigger iron accumulation and reduce lifespan. To evaluate molecular effects of iron chelator drugs as a potential PD therapy, we assessed fibroblasts by global proteome profiles and targeted transcript analyses. In mouse cells, iron shortage decreased protein abundance for iron-binding nucleotide metabolism enzymes (prominently XDH and ferritin homolog RRM2). It also decreased the expression of factors with a role for nucleotide surveillance, which associate with iron-sulfur-clusters (ISC), and are important for growth and survival. This widespread effect included prominently Nthl1-Ppat-Bdh2, but also mitochondrial Glrx5-Nfu1-Bola1, cytosolic Aco1-Abce1-Tyw5, and nuclear Dna2-Elp3-Pold1-Prim2. Incidentally, upregulated Pink1-Prkn levels explained mitophagy induction, the downregulated expression of Slc25a28 suggested it to function in iron export. The impact of PINK1 mutations in mouse and patient cells was pronounced only after iron overload, causing hyperreactive expression of ribosomal surveillance factor Abce1 and of ferritin, despite ferritin translation being repressed by IRP1. This misregulation might be explained by the deficiency of the ISC-biogenesis factor GLRX5. Our systematic survey suggests mitochondrial ISC-biogenesis and post-transcriptional iron regulation to be important in the decision, whether organisms undergo PD pathogenesis or healthy aging.

The kinesin-3, unc-104 regulates dendrite morphogenesis and synaptic development in Drosophila.

Kinesin-based transport is important for synaptogenesis, neuroplasticity, and maintaining synaptic function. In an anatomical screen of neurodevelopmental mutants, we identified the exchange of a conserved residue (R561H) in the forkhead-associated domain of the kinesin-3 family member Unc-104/KIF1A as the genetic cause for defects in synaptic terminal- and dendrite morphogenesis. Previous structure-based analysis suggested that the corresponding residue in KIF1A might be involved in stabilizing the activated state of kinesin-3 dimers. Herein we provide the first in vivo evidence for the functional importance of R561. The R561H allele (unc-104(bris)) is not embryonic lethal, which allowed us to investigate consequences of disturbed Unc-104 function on postembryonic synapse development and larval behavior. We demonstrate that Unc-104 regulates the reliable apposition of active zones and postsynaptic densities, possibly by controlling site-specific delivery of its cargo. Next, we identified a role for Unc-104 in restraining neuromuscular junction growth and coordinating dendrite branch morphogenesis, suggesting that Unc-104 is also involved in dendritic transport. Mutations in KIF1A/unc-104 have been associated with hereditary spastic paraplegia and hereditary sensory and autonomic neuropathy type 2. However, we did not observe synapse retraction or dystonic posterior paralysis. Overall, our study demonstrates the specificity of defects caused by selective impairments of distinct molecular motors and highlights the critical importance of Unc-104 for the maturation of neuronal structures during embryonic development, larval synaptic terminal outgrowth, and dendrite morphogenesis.