Oxidative stress (OS) and inflammation are two important and well-studied pathological hallmarks of neurodegenerative diseases (NDDs). Due to elevated oxygen consumption, the high presence of easily oxidizable polyunsaturated fatty acids and the weak antioxidant defenses, the brain is particularly vulnerable to oxidative injury. Uncertainty exists over whether these deficits contribute to the development of NDDs or are solely a consequence of neuronal degeneration. Furthermore, these two pathological hallmarks are linked, and it is known that OS can affect the inflammatory response. In this review, we will overview the last findings about these two pathways in the principal NDDs. Moreover, we will focus more in depth on amyotrophic lateral sclerosis (ALS) to understand how anti-inflammatory and antioxidants drugs have been used for the treatment of this still incurable motor neuron (MN) disease. Finally, we will analyze the principal past and actual clinical trials and the future perspectives in the study of these two pathological mechanisms.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the progressive loss of lower motor neurons, weakness and muscle atrophy. ALS lacks an effective cure and diagnosis is often made by exclusion. Thus, it is imperative to search for biomarkers. Biomarkers can help in understanding ALS pathomechanisms, identification of targets for treatment and development of effective therapies. Peripheral blood mononuclear cells (PBMCs) represent a valid source for biomarkers compared to cerebrospinal fluid, as they are simple to collect, and to plasma, because of the possibility of detecting lower expressed proteins. They are a reliable model for patients’ stratification. This review provides an overview on PBMCs as a potential source of biomarkers in ALS. We focused on altered RNA metabolism (coding/non-coding RNA), including RNA processing, mRNA stabilization, transport and translation regulation. We addressed protein abnormalities (aggregation, misfolding and modifications); specifically, we highlighted that SOD1 appears to be the most characterizing protein in ALS. Finally, we emphasized the correlation between biological parameters and disease phenotypes, as regards prognosis, severity and clinical features. In conclusion, even though further studies are needed to standardize the use of PBMCs as a tool for biomarker investigation, they represent a promising approach in ALS research.

Alzheimer’s disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches.

Sicily, situated at the heart of the Mediterranean Sea, has been a crossroads of people of different origins since the Paleolithic. To gain further insight into the genetic history of this island from a matrilineal viewpoint, we investigated 15 millennia of human mitogenome evolution. A unique Sicilian mitochondrial DNA (mtDNA) dataset, represented by 116 ancient mitogenomes (including two newly sequenced) collected from 16 archeological sites dating from 14,700 to 545 years ago, was compared with a collection of 236 modern mitogenomes covering all districts of the island. By integrating demographic modeling with phylogeographic analyses, we identified a statistically supported genetic discontinuity between the Paleolithic/Late Mesolithic and Early Neolithic periods and two mtDNA lineages (U5b and U8b/K) that specifically mark this transition. The extensive variation and lack of genetic structure among modern mitogenomes suggest the presence of a continuous, maternally inherited gene flow from different regions of Western Eurasia (since the Paleolithic) and Africa (since the Bronze Age).

The complexity of RNA metabolism has become crucial in neuromuscular diseases, especially for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Our goal was to search for possible pathways that differ between the two diseases, in which DMD develops a severe phenotype compared to BMD. In this work, we aimed to evaluate the transcriptomic profile in skeletal muscle biopsies derived from patients with either DMD or BMD. We collected RNA obtained from pediatric patients with DMD (n = 12) and with BMD (n = 6). Compared to patients with BMD, patients with DMD showed a particular activation of genes involved in collagen synthesis, extracellular matrix organization, and Oncostatin M-dependent pathways, important for fibrotic processes. This suggests that a more severe phenotype in patients with DMD compared to those with BMD may be due to greater deregulation of these pathways, reflecting the clinical picture of patients observed. Our results allowed us to highlight the molecular differences between the two phenotypic groups, shedding light on the pathways that make Duchenne dystrophy more severe than its counterpart does. This study provides preliminary insights into the difference in gene expression between the two groups and lays the basis for the identification of possible mechanisms that differentiate between the two diseases.

High-altitude adaptation in Andean populations has traditionally been studied through the lens of genetic variation, with limited exploration of epigenetic mechanisms such as DNA methylation. Here, we present the first whole-methylome data comparing Indigenous populations residing in high-altitude regions of the Ecuadorian Andes to those in low-altitude Peruvian Amazon regions bordering the Andes. By leveraging whole-methylome sequencing rather than methylation arrays, we achieved an unprecedented resolution of epigenetic variation, revealing novel insights into altitude-associated adaptations. We identified significant differentially methylated regions in genes involved in hypoxia response and skin pigmentation that differ from patterns previously observed in high-altitude Tibetan individuals [Lin et al. (Genome-wide DNA methylation landscape of four Chinese populations and epigenetic variation linked to Tibetan high-altitude adaptation. Science China Life Sciences 2023;66:2354–69. https://doi.org/10.1007/s11427-022-2284-8.)]. Our findings highlight the influence that altitude-specific environmental pressures, such as hypoxia and ultraviolet radiation, can have on the epigenetic landscapes observed between human populations. Importantly, we uncovered unique regulatory methylation signatures in the hypoxia response pathways of Andean populations, underscoring a distinct epigenetic trajectory compared to other high-altitude groups. This study represents a step forward in understanding Indigenous American genomic plasticity and demonstrates the value of whole-methylome data over methylation arrays in capturing the complex interplay between epigenetics and the environment. These results support a new approach to studying altitude plasticity and underscore the critical role of epigenetics in shaping population-specific cellular responses in Indigenous communities.