Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy

Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. One remarkable, yet unresolved, feature of SMA is that not all motor neurons are equally affected, with some populations displaying a robust resistance to the disease. Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. Comparative gene expression profiling of motor neurons innervating the extensor digitorum longus (disease-resistant), gastrocnemius (intermediate vulnerability), and tibialis anterior (vulnerable) muscles in mice revealed that disease susceptibility correlates strongly with a modified bioenergetic profile. Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. Moreover, targeting of a single bioenergetic protein, phosphoglycerate kinase 1 (Pgk1), was found to modulate motor neuron vulnerability in vivo. Knockdown of pgk1 alone was sufficient to partially mimic the SMA phenotype in wild-type zebrafish. Conversely, Pgk1 overexpression, or treatment with terazosin (an FDA-approved small molecule that binds and activates Pgk1), rescued motor axon phenotypes in SMA zebrafish. We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo

Improving Amendment

State constitutional amendment rules are often criticized for their poor design. The most common criticism is that the frequent use of direct democracy bypasses the virtues of representative decision making and effectively surrenders constitutional politics to well-financed special interests. Indeed, many initiative states need to improve the democratic quality of their amendment procedures. They need effective ways to foster constructive public deliberation, incentivize meaningful citizen participation, and provide checks on the influence of special interests. In this essay, I consider whether states might achieve some of those improvements if they changed the process for ratifying citizen-initiative amendments to require debate and approval by locally-elected governing bodies rather than a public referendum. The specific proposal that I explore is whether initiative states could improve their amendment processes by changing amendment rules to require ratification of citizen-initiatives by some majority of existing county governing bodies rather than a statewide referendum. Sending amendment ratification decisions to locally-elected bodies could have the beneficial effect of keeping constitutional decision-making close to citizens while at the same time retaining many of the virtues associated with representative decision-making. It might also help undermine special-interest capture by dividing the amendment power across numerous independently elected bodies rather than centralizing it within a state legislature or popular majority vote. Of course, a county-ratification model is not a panacea. There are many difficulties and costs associated with this approach. It might, for example, make the citizen-initiative too difficult to use, which would effectively shift all amendment power to the legislature. County representatives might also be ill-suited to decide statewide constitutional issues because of mismatched expertise and limited resources. A county-ratification model could also result in unconstitutional voter-dilution because of significant population differences between counties. These issues, among others, represent serious difficulties with the county-ratification model that cannot be overlooked. My goal in this essay is only to suggest that the county-ratification model deserves serious consideration as states struggle with how they might improve their amendment processes