Marcelo P. Coba

TL;DR: It is shown that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes, and among de novo variants associated with neurodevelopmental disorders, including schizophrenia.

Abstract: An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD

TL;DR: Bioinformatic and in vitro phosphorylation assays of peptide arrays suggest that a small number of kinases phosphorylate many proteins and that each substrate is phosphorylated by many kinases, which support a model where the synapse phosphoproteome is functionally organized into a highly interconnected signaling network.

TL;DR: In vivo data support the model that specific MAGUK proteins couple the NMDA receptor to distinct downstream signaling pathways that provide a mechanism for discriminating patterns of synaptic activity that lead to long-lasting changes in synaptic strength as well as distinct aspects of cognition in the mammalian nervous system.

TL;DR: Maps of molecular circuitry within the PSD are defined based on phosphorylation of postsynaptic proteins, which may provide new insights into disease mechanisms and new opportunities for drug discovery.