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.

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.

Angelman Syndrome (AS, MIM #105830) is a rare neurodevelopmental disorder caused by imprinting defects, marked by motor issues, intellectual disability, speech challenges, and seizures. The condition arises due to the loss of function in neurons of the maternally-inherited UBE3A gene, mapping in the imprinted chromosomal region 15q11.2-q13, which is caused by genetic and epigenetic mechanisms. UBE3A encodes an ubiquitin E3 ligase, essential for synaptic plasticity. Most studies on AS have been performed on animal models, while induced pluripotent stem cells (IPSCs), mainly from patients with deletions, are still in a limited number. Here we report on the generation and characterization of human cortical neurons derived from IPSCs of children representative of the main AS genotypes: 3 with 15q11–13 deletion, 4 with UBE3A mutations, 2 with uniparental disomy, and 2 with imprinting defects. During early neuronal differentiation, morphological analyses highlighted a reduced dendritic branching and an increase of thin filopodia, while migration assays revealed a reduction in neurite mobility in AS human neurons with deletion. At a later differentiation timepoint, the study of electrical activity revealed an impairment in neurons from AS patients. Basing of data of literature proving a role of JNK (c-Jun N-terminal kinase) signalling pathway in the filopodia formation and synaptic development, we examined the JNK deregulation in our cellular model. We found increased activation of JNK, and importantly the treatment with a JNK-inhibitor, D-JNKI1, partially corrected the neuronal morphological defects, notably reducing the number of immature protrusions, and defects in electrophysiological properties.