Cerebellar Purkinje cells (PCs) express a large amount of the ␥ isoform of protein kinase C (PKC␥) and a modest level of PKC␣. The PKC␥ is involved in the pruning of climbing fiber (CF) synapses from developing PCs, and PKC␣ plays a critical role in long-term depression (LTD) at parallel fiber (PF)-PC synapses. Moreover, the PKC signaling in PCs negatively modulates the nonselective transient receptor potential cation channel type 3 (TRPC3), the opening of which elicits slow EPSCs at PF-PC synapses. Autosomal dominant spinocerebellar ataxia type 14 (SCA14) is caused by mutations in PKC␥. To clarify the pathology of this disorder, mutant (S119P) PKC␥ tagged with GFP was lentivirally expressed in developing and mature mouse PCs in vivo, and the effects were assessed 3 weeks after the injection. Mutant PKC␥-GFP aggregated in PCs without signs of degeneration. Electrophysiology results showed impaired pruning of CF synapses from developing PCs, failure of LTD expression, and increases in slow EPSC amplitude. We also found that mutant PKC␥ colocalized with wild-type PKC␥, which suggests that mutant PKC␥ acts in a dominant-negative manner on wild-type PKC␥. In contrast, PKC␣ did not colocalize with mutant PKC␥. The membrane residence time of PKC␣ after depolarization-induced translocation, however, was significantly decreased when it was present with the mutant PKC␥ construct. These results suggest that mutant PKC␥ in PCs of SCA14 patients could differentially impair the membrane translocation kinetics of wild-type ␥ and ␣ PKCs, which would disrupt synapse pruning, synaptic plasticity, and synaptic transmission.

Using single-stranded adeno-associated virus serotype 9 (ssAAV9) vectors containing the neuron-specific synapsin-I promoter, we examined whether different administration routes (direct cerebellar cortical (DC), intrathecal (IT) and intravenous (IV) injections) could elicit specific transduction profiles in the CNS. The DC injection route robustly and exclusively transduced the whole cerebellum, whereas the IT injection route primarily transduced the cerebellar lobules 9 and 10 close to the injection site and the spinal cord. An IV injection in neonatal mice weakly and homogenously transduced broad CNS areas. In the cerebellar cortex, the DC and IT injection routes transduced all neuron types, whereas the IV injection route primarily transduced Purkinje cells. To verify the usefulness of this method, we generated a mouse model of spinocerebellar ataxia type 1 (SCA1). Mice that received a DC injection of the ssAAV9 vector expressing mutant ATXN1, a protein responsible for SCA1, showed the intranuclear aggregation of mutant ATXN1 in Purkinje cells, significant atrophy of the Purkinje cell dendrites and progressive motor deficits, which are characteristics of SCA1. Thus, ssAAV9-mediated transduction areas, levels, and cell types change depending on the route of injection. Moreover, this approach can be used for the generation of different mouse models of CNS/neurodegenerative diseases.

The sarcopenic phenotype is characterized by a reduction of muscle mass, a shift in fiber-type distribution, and reduced satellite cell regeneration. Sarcopenia is still a major challenge to healthy aging. Traditional Indonesian societies in Sulawesi island have been using nutmeg for maintaining health condition during aging. Interestingly, nutmeg has been known to stimulate peroxisome proliferator activated receptors γ (PPARγ) which may contribute to myogenesis process in cardiac muscle. There is limited information about the role of nutmeg extract into physiological health benefit during aging especially myogenesis process in skeletal muscle. In the present study, we want to explore the potential effect of nutmeg in preserving skeletal muscle mass of aging rats. Aging rats, 80 weeks old, were divided into two groups (control and nutmeg). Nutmeg extract was administered for 12 weeks by gavaging. After treatment, rats were anaesthesized, then soleus and gastrocnemius muscles were collected, weighted, frozen using liquid nitrogen, and stored at -80°C until use. We observed phenomenon that nutmeg increased a little but significant food consumption on week 12, but significant decrease in body weight on weeks 10 and 12 unexpectedly increased significantly in soleus muscle weight (p<0.05). Nutmeg extract increased significantly gene expression of myogenic differentiation (MyoD), paired box 7 (Pax7), myogenin, myosin heavy chain I (MHC I), and insulin-like growth factor I (p<0.01) in soleus muscle. Furthermore, nutmeg increased serine/threonine kinase (AKT) protein levels and activation of mammalian target of rapamycin (mTOR), inhibited autophagy activity, and stimulated or at least preserved muscle mass during aging. Taken together, nutmeg extract may increase muscle mass or prevent decrease of muscle wasting in soleus muscle by partly stimulating myogenesis, regeneration process, and preserving muscle mass via IGF-AKT-mTOR pathway leading to inhibition of autophagy activity during aging. This finding may reveal the potential nutmeg benefits as alternative supplement for preserving skeletal muscle mass and preventing sarcopenia in elderly.

Yes-associated protein (YAP) is one of the Hippo pathway's two effectors, a pathway associated with organ size control. Research on YAP has focused on its oncogenic potential. However, in cancer cells, aside from inducing growth, YAP was also found to regulate glucose metabolism. Therefore, we aimed to explore YAP's control of glucose metabolism and whether these findings are translatable to physiological conditions. We conducted a systematic review of the MEDLINE database through PubMed in April 2020 and repeated the search in September 2020. We found that YAP induced the transcriptional activity of most genes associated with glucose metabolism from enzymes to transport proteins. In glycolysis and gluconeogenesis, YAP upregulated all enzymes except for enolase and pyruvate kinase. Multiple research has also shown YAP's ability to regulate the expression of glucose transporter of the GLUT family. Additionally, glucose concentration, hypoxia, and hormones such as insulin and glucagon regulate YAP activity and depend on YAP to exert their biological activity. In this review, we have shown that YAP is a central regulator of glucose metabolism, controlling both enzymes and proteins involved in glucose transport. YAP is also situated strategically in several pathways controlling glucose and was found to mediate their effects. If these results were consistent in physiological conditions and across glucose-associated metabolic disturbances, then YAP may become a prospective therapeutic target.