The cyclin-dependent kinase 5 activators p35 and p39 interact with the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II and alpha-actinin-1 in a calcium-dependent manner

Cyclin-dependent kinase 5 (Cdk5) is a critical regulator of neuronal migration in the developing CNS, and recent studies have revealed a role for Cdk5 in synaptogenesis and regulation of synaptic transmission. Deregulation of Cdk5 has been linked to the pathology of neurodegenerative diseases such as Alzheimer\u27s disease. Activation of Cdk5 requires its association with a regulatory subunit, and two Cdk5 activators, p35 and p39, have been identified. To gain further insight into the functions of Cdk5, we identified proteins that interact with p39 in a yeast two-hybrid screen. In this study we report that alpha-actinin-1 and the alpha-subunit of Ca2+/calmodulin-dependent protein kinase II (CaMKIIalpha), two proteins localized at the postsynaptic density, interact with Cdk5 via their association with p35 and p39. CaMKIIalpha and alpha-actinin-1 bind to distinct regions of p35 and p39 and also can interact with each other. The association of CaMKIIalpha and alpha-actinin-1 to the Cdk5 activators, as well as to each other, is stimulated by calcium. Further, the activation of glutamate receptors increases the association of p35 and p39 with CaMKIIalpha, and the inhibition of CaMKII activation diminishes this effect. The glutamate-mediated increase in association of p35 and CaMKIIalpha is mediated in large part by NMDA receptors, suggesting that cross talk between the Cdk5 and CaMKII signal transduction pathways may be a component of the complex molecular mechanisms contributing to synaptic plasticity, memory, and learning

Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps

Newborn screening (NBS) identifies infants with specific congenital disorders for which earlier intervention cannot only prevent a lifetime of chronic disability but also, most importantly, save lives. In this article, we discuss complexities associated with NBS processes in the United States, with a focus on challenges in neuromuscular disorders. As new interventions for neuromuscular disorders become available, the clinical community must prepare to overcome the challenges of adding new diseases to screening panels and understand the rigorous evidence review at the federal level and the complex process of state-level implementation. In this regard, NBS programs for Pompe disease and spinal muscular atrophy can guide the path of Duchenne muscular dystrophy and other neuromuscular disorders as future candidates for NBS. The availability of advanced screening methods, the emergence of effective treatment, and the support of professional organizations may facilitate the expansion of NBS, such that an increasing number of infants can be identified in the newborn period who will benefit from life-saving interventions

Decreased Lin7b expression in layer 5 pyramidal neurons may contribute to impaired corticostriatal connectivity in huntington disease

Motor dysfunction, cognitive impairment, and regional cortical atrophy indicate cerebral cortical involvement in Huntington disease (HD). To address the hypothesis that abnormal corticostriatal connectivity arises from polyglutamine-related alterations in cortical gene expression, we isolated layer 5 cortical neurons by laser-capture microdissection and analyzed transcriptome-wide mRNA changes in them. Enrichment of transcription factor mRNAs including foxp2, tbr1, and neuroD6, and neurotransmission- and plasticity-related RNAs including sema5A, pclo, ntrk2, cntn1, and Lin7b were observed. Layer 5 motor cortex neurons of transgenic R6/2 HD mice also demonstrated numerous transcriptomic changes, including decreased expression of mRNAs encoding the Lin7 homolog b ([Lin7b] also known as veli-2 and mals2). Decreases in LIN7B and CNTN1 RNAs were also detected in human HD layer 5 motor cortex neurons. Lin7 homolog b, a scaffold protein implicated in synaptic plasticity, neurite outgrowth, and cellular polarity, was decreased at the protein level in layer 5 cortical neurons in R6/2 mice and human HD brains. Decreases in Lin7b and Lin7a mRNAs were detected in R6/2 cortex as early as 6 weeks of age, suggesting that this is an early pathogenetic event. Thus, decreased cortical LIN7 expression may contribute to abnormal corticostriatal connectivity in HD

234th ENMC International Workshop: Chaperone dysfunction in muscle disease Naarden, The Netherlands, 8\u201310 December 2017

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