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Mutations in Cu/Zn superoxide dismutase 1 (SOD1) lead to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease that disproportionately affects glutamatergic and cholinergic motor neurons. Previous work with SOD1 overexpression models supports a role for SOD1 toxic gain of function in ALS pathogenesis. However, the impact of SOD1 loss of function in ALS cannot be directly examined in overexpression models. In addition, overexpression may obscure the contribution of SOD1 loss of function in the degeneration of different neuronal populations. Here, we report the first single-copy, ALS knock-in models in C. elegans generated by transposon- or CRISPR/Cas9- mediated genome editing of the endogenous sod-1 gene. Introduction of ALS patient amino acid changes A4V, H71Y, L84V, G85R or G93A into the C. elegans sod-1 gene yielded single-copy/knock-in ALS SOD1 models. These differ from previously reported overexpression models in multiple assays. In single-copy/knock-in models, we observed differential impact of sod-1 ALS alleles on glutamatergic and cholinergic neurodegeneration. A4V, H71Y, G85R, and G93A animals showed increased SOD1 protein accumulation and oxidative stress induced degeneration, consistent with a toxic gain of function in cholinergic motor neurons. By contrast, H71Y, L84V, and G85R lead to glutamatergic neuron degeneration due to sod-1 loss of function after oxidative stress. However, dopaminergic and serotonergic neuronal populations were spared in single-copy ALS models, suggesting a neuronal-subtype specificity previously not reported in invertebrate ALS SOD1 models. Combined, these results suggest that knock-in models may reproduce the neurotransmitter-type specificity of ALS and that both SOD1 loss and gain of toxic function differentially contribute to ALS pathogenesis in different neuronal populations.

Spinal Muscular Atrophy (SMA) is caused by diminished Survival of Motor Neuron (SMN) protein, leading to neuromuscular junction (NMJ) dysfunction and spinal motor neuron (MN) loss. Here, we report that reduced SMN function impacts the action of a pertinent microRNA and its mRNA target in MNs. Loss of the C. elegans SMN ortholog, SMN-1, causes NMJ defects. We found that increased levels of the C. elegans Gemin3 ortholog, MEL-46, ameliorates these defects. Increased MEL-46 levels also restored perturbed microRNA (miR-2) function in smn-1(lf) animals. We determined that miR-2 regulates expression of the C. elegans M2 muscarinic receptor (m2R) ortholog, GAR-2. GAR-2 loss ameliorated smn-1(lf) and mel-46(lf) synaptic defects. In an SMA mouse model, m2R levels were increased and pharmacological inhibition of m2R rescued MN process defects. Collectively, these results suggest decreased SMN leads to defective microRNA function via MEL-46 misregulation, followed by increased m2R expression, and neuronal dysfunction in SMA. Spinal muscular atrophy is a genetic disease that causes muscles to gradually weaken. In people with the disease, the nerve cells that control the movement of muscles – called motor neurons – deteriorate over time, hindering the person’s mobility and shortening their life expectancy. Spinal muscular atrophy is usually caused by genetic faults affecting a protein called SMN (which is short for “Survival of motor neuron”) and recent research suggested that disrupting this protein alters the function of short pieces of genetic material called microRNAs. However, the precise role that microRNAs play in the disease and their connection to the SMN protein was not clear. MicroRNAs interfere with the production of proteins by disrupting molecules called messenger RNAs, which are temporary strings of genetic code that carry the instructions for making protein. By disrupting messenger RNAs, microRNAs can delay or halt the production of specific proteins. This is an important part of the normal behavior of a cell, but disturbing the activity of microRNAs can lead to an unwanted rise or fall in crucial proteins. O’Hern et al. made use of engineered nematode worms and mice that share genetic features with spinal muscular atrophy patients, including disruption of the gene responsible for producing the SMN protein. These animal models of the disease were used to examine the relationship between decreased SMN levels and microRNAs in motor neurons. The experiments showed that reduced SMN activity affects a specific microRNA, which in turn causes motor neurons to produce more of a protein called m2R. This protein is a receptor for a molecule, called acetylcholine, which motor neurons use to send signals to muscle cells. Increased m2R may be detrimental to motor neurons. As such, O’Hern et al. decreased m2R protein activity to determine whether this could reverse the defects in motor neurons that arise in the animal models of the disease. Indeed, blocking this receptor rescued some of the defects seen in the animal models, supporting the link to spinal muscular atrophy. Several treatments that block m2R are already available to treat other conditions. As such, the next step is to determine whether these existing treatments are able to protect mice models of spinal muscular atrophy against muscle deterioration or increase their lifespan. If successful, this could open new avenues for the development of treatments in people.

The Forum on China-African Cooperation (FOCAC) was established in the year 2000 by the government of China. It aims at furthering existing bilateral relations and cooperation with African countries and Nigeria in particular. As a mechanism for coordinating interventionist development initiatives in the areas of infrastructure, security cooperation, trade and investment relations, FOCAC aims at imbuing a ‘win-win’ agenda for parties within the forum. FOCAC operates with the drive for interdependence between actors. This renewed vigour between China and Africa seeks to douse the schisms and alleged ulterior motives of China in her relations with African countries. It is against this background that the study examined the general framework of Sino-Nigeria cooperation and commitment within the context of FOCAC; dissect the contentious issues of cooperation or re-colonization; investigate the issues in Nigeria-China infrastructure financing cooperation and commitments; identify the impact and utility of Nigeria-China military cooperation and ascertain the basis for the seeming hysteria in trade relations between Nigeria and China. Relying on the qualitative methodology, primary data was generated for the study from interview of forty-nine purposively selected key informants from proximate policy makers and implementers drawn from the Ministries of Transportation, Foreign Affairs, Finance, Trade and Investment, Nigerian Institute of International Affairs, Legislators (House Committee on Treaties, Protocols and Agreements) the Civil Society and the academia. Data obtained were thematically analysed with the aid of researcher-reflexivity. Findings from the study indicates that the Forum’s summits and conference deliberations from the Beijing Declaration in 2000, Addisa Ababa Action Plan (2003), Beijing Action Plan (2006), Sharm El-Sheikh Action Plan (2009), Beijing Plan of Action (2012), Johannesburg Action Plan (2015) and Beijing Plan of Action (2018) have radically improved China’s interventions in the areas of infrastructure, security and trade and investment cooperation and commitments. The study recommends amongst other things that in dealing with China within the FOCAC framework, the Nigerian government should project internal cohesion erected on a more result-driven national administrative framework, a workable national agenda and developmental philosophy that will project the country as a conscious partner within the ambit of the corporate interdependence school with clear objectives.