Mitigating aberrant Cdk5 activation alleviates mitochondrial defects and motor neuron disease symptoms in spinal muscular atrophy.

Spinal muscular atrophy (SMA), the top genetic cause of infant mortality, is characterized by motor neuron degeneration. Mechanisms underlying SMA pathogenesis remain largely unknown. Here, we report that the activity of cyclin-dependent kinase 5 (Cdk5) and the conversion of its activating subunit p35 to the more potent activator p25 are significantly up-regulated in mouse models and human induced pluripotent stem cell (iPSC) models of SMA. The increase of Cdk5 activity occurs before the onset of SMA phenotypes, suggesting that it may be an initiator of the disease. Importantly, aberrant Cdk5 activation causes mitochondrial defects and motor neuron degeneration, as the genetic knockout of p35 in an SMA mouse model rescues mitochondrial transport and fragmentation defects, and alleviates SMA phenotypes including motor neuron hyperexcitability, loss of excitatory synapses, neuromuscular junction denervation, and motor neuron degeneration. Inhibition of the Cdk5 signaling pathway reduces the degeneration of motor neurons derived from SMA mice and human SMA iPSCs. Altogether, our studies reveal a critical role for the aberrant activation of Cdk5 in SMA pathogenesis and suggest a potential target for therapeutic intervention.

Global citizenship education through curriculum-as-relations.

The Covid-19 pandemic was a reminder of the importance of increasing connectivity amidst the accelerated rate of changes and disruptive events of our era. The need and the rationale for global citizenship education (GCED) were ever more emphasized by many educational organizations, including UNESCO. This article reviews the GCED discourses conceptualizing global competence as instrumental action and a binary view of global-local relations. In turn, the article proposes the idea of curriculum-as-relations for GCED. Curriculum-as-relations conceptualizes competence as situated praxis and focuses on providing authentic critical-translocal learning. Authentic critical-translocal learning through the strategy of comparison offers an alternative view of global-local relations as "articulated moments created by situated praxis". This new understanding of global-local relations may help different stakeholders to imagine GCED curricula beyond a Tylerian instrumentalist, ends-means orientation of curriculum.