Phosphorylation of α-synuclein is crucial in compensating for proteasomal dysfunction

α-Synuclein can be degraded by both the ubiquitin-proteasomal system and the chaperone-lysosomal system. However, the switching mechanism between the two pathways is not clearly understood. In our study, we investigated the mutual association between the binding of α-synuclein to heat shock cognate 70 and the lysosomal translocation of α-synuclein. Tyrosine phosphorylation of Y136 on α-synuclein increased when it bound to heat shock protein 70. We also found that tyrosine phosphorylation of α-synuclein can be regulated by focal adhesion kinase pp125 and protein tyrosine phosphatase 1B. Furthermore, protein tyrosine phosphatase 1B inhibitor protected dopaminergic neurons against cell death and rescued rotarod performance in a Parkinson's disease animal model. This study provides evidence that the regulation of Y136 phosphorylation of α-synuclein can improve behavioral performance and protect against neuronal death by promoting the turnover of lysosomal degradation of α-synuclein. As a result, protein tyrosine phosphatase 1B inhibitor may be used as a potential therapeutic agent against Parkinson's disease

WNT signalling control by KDM5C during development affects cognition

Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Specifically, there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis. Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells and to induce these changes in wild-type cells. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. The results also increase our general understanding of memory and anxiety formation, with the identification of WNT functioning in a transient nature to affect long-lasting cognitive function

Sodium Channel SCN3A (Na(V)1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development

Channelopathies are disorders caused by abnormal ion channel function in differentiated excitable tissues. We discovered a unique neurodevelopmental channelopathy resulting from pathogenic variants in SCN3A, a gene encoding the voltage-gated sodium channel Na(V)1.3. Pathogenic Na(V)1.3 channels showed altered biophysical properties including increased persistent current. Remarkably, affected individuals showed disrupted folding (polymicrogyria) of the perisylvian cortex of the brain but did not typically exhibit epilepsy; they presented with prominent speech and oral motor dysfunction, implicating SCN3A in prenatal development of human cortical language areas. The development of this disorder parallels SCN3A expression, which we observed to be highest early in fetal cortical development in progenitor cells of the outer subventricular zone and cortical plate neurons and decreased postnatally, when SCN1A (Na(V)1.1) expression increased. Disrupted cerebral cortical folding and neuronal migration were recapitulated in ferrets expressing the mutant channel, underscoring the unexpected role of SCN3A in progenitor cells and migrating neurons.Peer reviewe

WNT signalling control by KDM5C during development affects cognition

Although KDM5C is one of the most frequently mutated genes in X-linked intellectual disability1, the exact mechanisms that lead to cognitive impairment remain unknown. Here we use human patient-derived induced pluripotent stem cells and Kdm5c knockout mice to conduct cellular, transcriptomic, chromatin and behavioural studies. KDM5C is identified as a safeguard to ensure that neurodevelopment occurs at an appropriate timescale, the disruption of which leads to intellectual disability. Specifically, there is a developmental window during which KDM5C directly controls WNT output to regulate the timely transition of primary to intermediate progenitor cells and consequently neurogenesis. Treatment with WNT signalling modulators at specific times reveal that only a transient alteration of the canonical WNT signalling pathway is sufficient to rescue the transcriptomic and chromatin landscapes in patient-derived cells and to induce these changes in wild-type cells. Notably, WNT inhibition during this developmental period also rescues behavioural changes of Kdm5c knockout mice. Conversely, a single injection of WNT3A into the brains of wild-type embryonic mice cause anxiety and memory alterations. Our work identifies KDM5C as a crucial sentinel for neurodevelopment and sheds new light on KDM5C mutation-associated intellectual disability. The results also increase our general understanding of memory and anxiety formation, with the identification of WNT functioning in a transient nature to affect long-lasting cognitive function

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus.

The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.(LM2018129 funded by MEYS CR), Czech Centre for Phenogenomics (LM2015040), Higher quality and capacity of transgenic model breeding (by MEYS and ERDF, OP RDI CZ.1.05/2.1.00/19.0395), Czech Centre for Phenogenomics: developing towards translation research (by MEYS and ESIF, OP RDE CZ.02.1.01/0.0/0.0/16_013/0001789), BCH viral core for AAV production. The collaboration between Masaryk University and Karolinska Institutet (KI-MU program), was co-financed by the European Social Fund and the state budget of the Czech Republic (CZ.1.07/2.3.00/20.0180). Funding to the VB lab was obtained from Neuron Fund for Support of Science (23/2016), and Czech Science Foundation (GA17- 16680S). Work in the EA lab was supported by the Swedish Research Council (VR projects: DBRM, 2011-3116, 2011-3318 and 2016-01526), Swedish Foundation for Kaiser et al.,Strategic Research (SRL program and SLA SB16-0065), European Commission (NeuroStemcellRepair), Karolinska Institutet (SFO Strat Regen, Senior grant 2018), Hjärnfonden (FO2015:0202 and FO2017-0059) and Cancerfonden (CAN 2016/572) foundations. KK was supported by Masaryk University (MUNI/E/0965/2016). RvA acknowledges funding support from the University of Amsterdam (MacGillavry fellowship), KWF Kankerbestrijding (Dutch Cancer Society, career development award ANW 2013-6057) and NWO (Netherlands Science Foundation, VIDI 864.13.002). Work in the OM lab is supported by the Czech Science Foundation (18- 00514S). ZK acknowledges funding support from GACR 18-20759S. RA Barker is supported by an NIHR funded Biomedical Research Centre at Cambridge University Hospital and the WT-MRC Cambridge Stem Cell Institute. The Lehtinen laboratory was supported by the Reagan Sloane Shanley Research Internship (ND), OFD/BTREC/CTREC Faculty Development Fellowship Award (RMF), NIH R01 NS088566 (MKL), the New York Stem Cell Foundation (MKL); and BCH IDDRC 1U54HD090255. MK Lehtinen is a New York Stem Cell Foundation – Robertson Investigator

A cellular and spatial map of the choroid plexus across brain ventricles and ages

The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas of each ChP in the developing, adult, and aged mouse brain. We delineate diverse cell types, subtypes, cell states, and expression programs in epithelial and mesenchymal cells across ages and ventricles. In the developing ChP, we predict a common progenitor pool for epithelial and neuronal cells, validated by lineage tracing. Epithelial and fibroblast cells show regionalized expression by ventricle, starting at embryonic stages and persisting with age, with a dramatic transcriptional shift with maturation, and a smaller shift in each aged cell type. With aging, epithelial cells upregulate host-defense programs, and resident macrophages upregulate interleukin-1β (IL-1β) signaling genes. Our atlas reveals cellular diversity, architecture and signaling across ventricles during development, maturation, and aging of the ChP-brain barrier