Miguel Chillón

As advances in neurobiology have accelerated over the past decade, our understanding of pediatric neurodevelopmental pathologies has been transformed, revealing how intricate the developing brain c...

Coronaviruses genomes are enriched in suboptimal A- and U-ending codons, which are typically associated with reduced translation efficiency due to limited cognate tRNA availability. How coronavirus efficiently express their proteins despite this limitation remains unclear. By analyzing their codon usage, we identify four tRNA modifications—inosine (I), queuosine (Q), 5-methylcarboxymethyluridine/ 5-methylcarboxymethyl-2-thiouridine (mcm ⁵ U/mcm ⁵ s ² U), and 5-methylcytidine/ 5-formylcytidine (m ⁵ C/f ⁵ C)—as essential for decoding their suboptimal codons. Notably, SARS-CoV-2 and HCoV-OC43 infections, representing severe and mild human infections, respectively, reprogram these modifications to favor viral protein synthesis. Mechanistically, this reprogramming was driven by altered expression of the corresponding tRNA modifying enzymes. Since both viruses induced DNA damage and oxidative stress—known to similarly alter Q, mcm ⁵ U/mcm ⁵ s ² U, and m ⁵ C/f ⁵ C modifications to favor expression of stress response proteins—our findings support that coronavirus genomes have adapted to the tRNA modification landscape under stress conditions. Overall, coronaviruses orchestrate a codon-specific reprogramming of the host tRNA modification landscape, highlighting a conserved strategy that optimizes translation efficiency and represents a promising target for pan-coronavirus antiviral therapy development.

α-Klotho is a multifunctional protein widely recognized for its anti-aging and neuroprotective properties. This study investigates the expression and localization of the secreted Klotho (s-KL) isoform in the human brain and its potential role in Alzheimer’s disease. Using RT-qPCR, we observed that the s-KL transcript predominates over the membrane-bound KL (m-KL) in multiple brain regions, a pattern consistent in macaques and lemurs. Immunohistochemistry and immunoprecipitation assays confirmed the presence of the s-KL protein in human and mouse brain parenchyma, revealing species-specific cellular localization. In human cerebrospinal fluid (CSF), s-KL constitutes ∼28% of total KL, with levels significantly reduced in mild dementia-AD patients. These findings underscore s-KL’s potential neuroprotective role and highlight its differential regulation and expression during AD progression.

There is a pressing need for the development, characterization, and standardization of animal models of Parkinson’s disease (PD) that properly mimic the cardinal features of this disorder, comprising both the motor phenotype and neuropathological signatures. In the past few years, animal modeling has moved from neurotoxin-based approaches toward viral vectors carrying a given genetic payload of interest. Here, to induce pigmentation of the mouse brain upon systemic delivery, we took advantage of a modified adeno-associated viral vector capsid engineered to bypass the blood-brain barrier and coding for the human tyrosinase gene (AAV9-P31-hTyr). Obtained results revealed an ongoing pigmentation of catecholaminergic centers related to the pathophysiology of PD, such as the substantia nigra pars compacta, ventral tegmental area, and locus coeruleus. Moreover, pigmented dopaminergic neurons exhibited Lewy body-like intracytoplasmic inclusions, a progressive nigrostriatal degeneration, and a time-dependent PD motor phenotype. The bilateral pigmented mouse model of PD generated this way is highly reproducible, does not require stereotaxic surgery for viral vector deliveries, and opens unprecedented possibilities for preclinical testing of therapeutic candidates designed to reduce disease progression rates.