As the level of interest in aging research increases, there is a growing number of geroprotectors, or therapeutic interventions that aim to extend the healthy lifespan and repair or reduce aging-related damage in model organisms and, eventually, in humans. There is a clear need for a manually-curated database of geroprotectors to compile and index their effects on aging and age-related diseases and link these effects to relevant studies and multiple biochemical and drug databases. Here, we introduce the first such resource, Geroprotectors (http://geroprotectors.org). Geroprotectors is a public, rapidly explorable database that catalogs over 250 experiments involving over 200 known or candidate geroprotectors that extend lifespan in model organisms. Each compound has a comprehensive profile complete with biochemistry, mechanisms, and lifespan effects in various model organisms, along with information ranging from chemical structure, side effects, and toxicity to FDA drug status. These are presented in a visually intuitive, efficient framework fit for casual browsing or in-depth research alike. Data are linked to the source studies or databases, providing quick and convenient access to original data. The Geroprotectors database facilitates cross-study, cross-organism, and cross-discipline analysis and saves countless hours of inefficient literature and web searching. Geroprotectors is a one-stop, knowledge-sharing, time-saving resource for researchers seeking healthy aging solutions.

Mutations to the RNA binding protein, fused in sarcoma (FUS) occur in ~5% of familial ALS and FUS-positive cytoplasmic inclusions are commonly observed in these patients. Altered RNA metabolism is increasingly implicated in ALS, yet it is not understood how the specificity with which FUS interacts with RNA in the cytoplasm can affect its aggregation in vivo. To further understand this, we expressed, in mice, a form of FUS (FUS ΔRRMcyt) that lacked the RNA recognition motif (RRM), thought to impart specificity to FUS-RNA interactions, and carried an ALS-associated point mutation, R522G, retaining the protein in the cytoplasm. Here we report the phenotype and results of histological assessment of the brain of transgenic mice expressing this isoform of FUS. Results demonstrated that neuronal expression of FUS ΔRRMcyt caused early lethality often preceded by severe tremor. Large FUS-positive cytoplasmic inclusions were found in many brain neurons; however, neither neuronal loss nor neuroinflammatory response was observed. In conclusion, the extensive FUS proteinopathy and severe phenotype of these mice suggests that affecting the interactions of FUS with RNA in vivo may augment its aggregation in the neuronal cytoplasm and the severity of disease processes.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease caused by the selective death of motor neurons. An important component in the ALS pathogenesis is the aggregation of proteins prone to conformational changes and the formation of characteristic intracellular histopathological inclu sions, on the basis of which this disease was attributed to the group of proteopathies [1]. In addition to the already known gene SOD1, recent medical genetic studies have identified a number of other genes whose mutations lead to the formation of pathogenic forms of their encoded proteins and development a neurode generative process with motoneuron lesions [2].In the sporadic ALS forms, these proteins were also found in the histopathological inclusions of the autopsy material of ALS patients. Moreover, studies performed in experimental models of ALS in trans genic mice and cell cultures provided evidence that the pathological picture of proteopathy characteristic of ALS can be reproduced in the case of metabolic disor der of only one of the key proteins [3].When studying the mechanisms of proteopathies associated with ALS and frontotemporal degenera tion, a new type of molecular cellular pathology was described. This pathology is caused by the dysfunction of the DNA/RNA binding proteins TDP43 and FUS (fused in sarcoma), which results in the inability of these proteins to form physiologically active, easily dissociating complexes with RNA (RNP). Instead, these proteins form stable RNA free structures with stably deposited aggregated forms of TDP43 and FUS proteins. This process is accompanied by changes in the intracellular compartmentalization of TDP43 and FUS and their accumulation in the pathogenic inclu sions in the cytoplasm [4][5][6][7].To model the proteopathy with the FUS protein, the aberrant forms of the FUS protein that were able to effectively form protein inclusions in cell cultures, similar to those detected in the autopsy material of ALS patients, were obtained [8]. It was found that the removal of the nuclear localization signal together with the C terminal region, which is significant for the conformational stability of the protein molecule, leads to the development of proteopathy with the involve ment of the FUS protein [5,6]. In the sequences of the gene encoding these protein regions, the largest num ber of mutations association with the hereditary forms of ALS and frontotemporal degeneration was detected. On the basis of such aberrant form of FUS, a transgenic model of proteopathy (fusopathy) was developed. Mice of this transgenic line were charac terized by the formation of histopathological inclu sions in the nervous system tissues and the develop ment of neurodegenerative process accompanied by a progressive loss of motor neurons [9]. These trans genic mice were used in this work to study the neuro protective effect of a compound of the gamma carbo line group on the progression of the model neurode generative process accompanied by primary lesion of motor neurons. It was previously shown t...

Dimebon leads to an increase in the duration of presymptomatic stage and delays the manifestation of clinical symptoms. The changes in the dynamics of the pathological process in the symptomatic stage are not detected.