New Views of the DNA Repair Protein Ataxia-Telangiectasia Mutated in Central Neurons: Contribution in Synaptic Dysfunctions of Neurodevelopmental and Neurodegenerative Diseases.

Ataxia-Telangiectasia Mutated (ATM) is a serine/threonine protein kinase principally known to orchestrate DNA repair processes upon DNA double-strand breaks (DSBs). Mutations in the Atm gene lead to Ataxia-Telangiectasia (AT), a recessive disorder characterized by ataxic movements consequent to cerebellar atrophy or dysfunction, along with immune alterations, genomic instability, and predisposition to cancer. AT patients show variable phenotypes ranging from neurologic abnormalities and cognitive impairments to more recently described neuropsychiatric features pointing to symptoms hardly ascribable to the canonical functions of ATM in DNA damage response (DDR). Indeed, evidence suggests that cognitive abilities rely on the proper functioning of DSB machinery and specific synaptic changes in central neurons of ATM-deficient mice unveiled unexpected roles of ATM at the synapse. Thus, in the present review, upon a brief recall of DNA damage responses, we focus our attention on the role of ATM in neuronal physiology and pathology and we discuss recent findings showing structural and functional changes in hippocampal and cortical synapses of AT mouse models. Collectively, a deeper knowledge of ATM-dependent mechanisms in neurons is necessary not only for a better comprehension of AT neurological phenotypes, but also for a higher understanding of the pathological mechanisms in neurodevelopmental and degenerative disorders involving ATM dysfunctions.

Lost in HELLS: Disentangling the mystery of SALNR existence in senescence cellular models.

Long non-coding RNAs (lncRNAs) have emerged as key regulators of cellular senescence by transcriptionally and post-transcriptionally modulating the expression of many important genes involved in senescence-associated pathways and processes. Among the different lncRNAs associated to senescence, Senescence Associated Long Non-coding RNA (SALNR) was found to be down-regulated in different cellular models of senescence. Since its release in 2015, SALNR has not been annotated in any database or public repository, and no other experimental data have been published. The SALNR sequence is located on the long arm of chromosome 10, at band 10q23.33, and it overlaps the 3' end of the HELLS gene. This investigation helped to unravel the mystery of the existence of SALNR by analyzing publicly available short- and long-read RNA sequencing data sets and RT-PCR analysis in human tissues and cell lines. Additionally, the expression of HELLS has been studied in cellular models of replicative senescence, both in silico and in vitro. Our findings, while not supporting the actual existence of SALNR as an independent transcript in the analyzed experimental models, demonstrate the expression of a predicted HELLS isoform entirely covering the SALNR genomic region. Furthermore, we observed a strong down-regulation of HELLS in senescent cells versus proliferating cells, supporting its role in the senescence and aging process.

Synovial Fluid-Derived Extracellular Vesicles of Patients with Arthritides Contribute to Hippocampal Synaptic Dysfunctions and Increase with Mood Disorders Severity in Humans.

Arthritides are a highly heterogeneous group of disorders that include two major clinical entities, localized joint disorders such as osteoarthritis (OA) and systemic autoimmune-driven diseases such as rheumatoid arthritis (RA). Arthritides are characterized by chronic debilitating musculoskeletal conditions and systemic chronic inflammation. Poor mental health is also one of the most common comorbidities of arthritides. Depressive symptoms which are most prevalent, negatively impact patient global assessment diminishing the probability of achieving the target of clinical remission. Here, we investigated new insights into mechanisms that link different joint disorders to poor mental health, and to this issue, we explored the action of the synovial fluid-derived extracellular vesicles (EVs) on neuronal function. Our data show that the exposure of neurons to different concentrations of EVs derived from both RA and OA synovial fluids (RA-EVs and OA-EVs) leads to increased excitatory synaptic transmission but acts on specific modifications on excitatory or inhibitory synapses, as evidenced by electrophysiological and confocal experiments carried out in hippocampal cultures. The treatment of neurons with EVs membrane is also responsible for generating similar effects to those found with intact EVs suggesting that changes in neuronal ability arise upon EVs membrane molecules' interactions with neurons. In humans with arthritides, we found that nearly half of patients (37.5%) showed clinically significant psychiatric symptoms (CGIs score ≥ 3), and at least mild anxiety (HAM-A ≥ 7) or depression (MADRS and HAM-D ≥ 7); interestingly, these individuals revealed an increased concentration of synovial EVs. In conclusion, our data showing opposite changes at the excitatory and inhibitory levels in neurons treated with OA- and RA-EVs, lay the scientific basis for personalized medicine in OA and RA patients, and identify EVs as new potential actionable biomarkers in patients with OA/RA with poor mental health.