RESUMEN
Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2 -targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.
RESUMEN
Limited work has examined how self-affirmation might lead to positive outcomes beyond the maintenance of a favorable self-image. To address this gap in the literature, we conducted two studies in two cultures to establish the benefits of self-affirmation for psychological well-being. In Study 1, South Korean participants who affirmed their values for 2 weeks showed increased eudaimonic well-being (need satisfaction, meaning, and flow) relative to control participants. In Study 2, U.S. participants performed a self-affirmation activity for 4 weeks. Extending Study 1, after 2 weeks, self-affirmation led both to increased eudaimonic well-being and hedonic well-being (affect balance). By 4 weeks, however, these effects were non-linear, and the increases in affect balance were only present for vulnerable participants-those initially low in eudaimonic well-being. In sum, the benefits of self-affirmation appear to extend beyond self-protection to include two types of well-being.