AUTS2 Governs Cerebellar Development, Purkinje Cell Maturation, Motor Function and Social Communication

Autism susceptibility candidate 2 (AUTS2), a risk gene for autism spectrum disorders (ASDs), is implicated in telencephalon development. Because AUTS2 is also expressed in the cerebellum where defects have been linked to ASDs, we investigated AUTS2 functions in the cerebellum. AUTS2 is specifically localized in Purkinje cells (PCs) and Golgi cells during postnatal development. Auts2 conditional knockout (cKO) mice exhibited smaller and deformed cerebella containing immature-shaped PCs with reduced expression of Cacna1a. Auts2 cKO and knock-down experiments implicated AUTS2 participation in elimination and translocation of climbing fiber synapses and restriction of parallel fiber synapse numbers. Auts2 cKO mice exhibited behavioral impairments in motor learning and vocal communications. Because Cacna1a is known to regulate synapse development in PCs, it suggests that AUTS2 is required for PC maturation to elicit normal development of PC synapses and thus the impairment of AUTS2 may cause cerebellar dysfunction related to psychiatric illnesses such as ASDs

GSK-3β Regulates Phosphorylation of CRMP-2 and Neuronal Polarity

AbstractNeurons are highly polarized and comprised of two structurally and functionally distinct parts, an axon and dendrites. We previously showed that collapsin response mediator protein-2 (CRMP-2) is critical for specifying axon/dendrite fate, possibly by promoting neurite elongation via microtubule assembly. Here, we showed that glycogen synthase kinase-3β (GSK-3β) phosphorylated CRMP-2 at Thr-514 and inactivated it. The expression of the nonphosphorylated form of CRMP-2 or inhibition of GSK-3β induced the formation of multiple axon-like neurites in hippocampal neurons. The expression of constitutively active GSK-3β impaired neuronal polarization, whereas the nonphosphorylated form of CRMP-2 counteracted the inhibitory effects of GSK-3β, indicating that GSK-3β regulates neuronal polarity through the phosphorylation of CRMP-2. Treatment of hippocampal neurons with neurotrophin-3 (NT-3) induced inactivation of GSK-3β and dephosphorylation of CRMP-2. Knockdown of CRMP-2 inhibited NT-3-induced axon outgrowth. These results suggest that NT-3 decreases phosphorylated CRMP-2 and increases nonphosphorylated active CRMP-2, thereby promoting axon outgrowth

Novel FABP3 ligand, HY-11-9, ameliorates neuropathological deficits in MPTP-induced Parkinsonism in mice

Parkinson's disease (PD) is characterized by dopaminergic (DAergic) neuronal loss in the substantia nigra pars compacta (SNpc), resulting from α-synuclein (αSyn) toxicity. We previously reported that αSyn oligomerization and toxicity are regulated by the fatty-acid binding protein 3 (FABP3), and the therapeutic effects of the FABP3 ligand, MF1, was successfully demonstrated in PD models. Here, we developed a novel and potent ligand, HY-11-9, which has a higher affinity for FABP3 (Kd = 11.7 ± 8.8) than MF1 (Kd = 302.8 ± 130.3). We also investigated whether the FABP3 ligand can ameliorate neuropathological deterioration after the onset of disease in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Motor deficits were observed two weeks after MPTP treatment. Notably, oral administration of HY-11-9 (0.03 mg/kg) improved motor deficits in both beam-walking and rotarod tasks, whereas MF1 failed to improve the motor deficits in both tasks. Consistent with the behavioral tasks, HY-11-9 recovered dopamine neurons from MPTP toxicity in the substantia nigra and ventral tegmental areas. Furthermore, HY-11-9 reduced the accumulation of phosphorylated-serine129-α-synuclein (pS129-αSyn) and colocalization with FABP3 in tyrosine hydroxylase (TH)-positive DA neurons in the PD mouse model. Overall, HY-11-9 significantly improved MPTP-induced behavioral and neuropathological deterioration, suggesting that it may be a potential candidate for PD therapy

Vimentin-Ser82 as a memory phosphorylation site in astrocytes

In astrocytes, the PGF(2 alpha) or ionomycin treatment induces the phosphorylation at Ser38 and Ser82 of vimentin, a type III intermediate filament, by Ca2+/calmodulin-dependent protein kinase II (CaMKII). We found here that vimentin phospho-Ser82 was dephosphorylated much slower than phospho-Ser38. Vimentin phospho-Ser38 was dephosphorylated quickly by purified PP1 catalytic subunit (PP1c) in vitro, whereas phospho-Ser82 was insensitive to PP1c. Because PP1c directly bound to vimentin through a VxF motif (Val83-Asp84-Phe85), the PP1c active site appeared to be unable to approach phospho-Ser82, leading to the prolongation of the phosphorylation at Ser-82. In astrocytes, PP1c alpha was in vivo associated with vimentin filaments. The repetitive treatment by ionomycin at a short interval resulted in the sustained elevation of Ser82 phosphorylation, leading to the marked disassembly of vimentin filaments. Taken together, these results suggest that vimentin is a novel member of binding partner of PP1c in astrocytes, and vimentin-Ser82 may act as a memory phosphorylation site