Biology subjects

Vuono, R.

Publications and source records attributed to Vuono, R..

3 recordsLinked to original sources

bioRxiv2025

Tau oligomers can occur in human brains within days of a single traumatic brain injury

Traumatic brain injury (TBI) is a major risk factor for Alzheimers disease (AD), yet the early molecular events linking the two remain unclear. Neurofibrillary tangles (NFTs), a hallmark of AD, are observed in individuals with a history of single or repetitive head injury. Animal studies show that tau oligomers, the toxic species preceding the NFTs, appear shortly after TBI, but corresponding human data are lacking. Here, we investigated tau changes in the brains of individuals who died shortly after TBI compared to those surviving long-term. We report abnormal tau oligomers in the brain of short-term survivors whereas NFTs were the main feature in long-term survivors. These findings support a model where TBI triggers early tau oligomers formation that spread through a prion-like mechanism, seeding tau pathology and contributing to late-onset AD. The novel identification of tau oligomers in acute TBI reveals potential early disease mechanisms and therapeutic targets for AD prevention. Importance statementBy revealing a potential early disease mechanism of Alzheimers disease (AD), this study represents a major breakthrough in our understanding, treatment and prevention of the disease. To our knowledge, this is the first report of tau oligomers in the brain of individuals suffering acute Traumatic Brain Injury (TBI). This is an important finding considering that TBI is a major risk factor of AD and tau oligomers are thought to be the most toxic species preceding tau pathology, a characteristic signature of AD. The identification of these early tau-related events after TBI provides insight into potential early AD mechanisms and offers a unique opportunity for early therapeutic intervention and prevention.

neuroscience↗

bioRxiv2021

Age-related pathological impairments in induced neurons derived from patients with idiopathic Parkinson's disease

Understanding the pathophysiology of Parkinsons disease has been hampered by the lack of models that recapitulate all the critical factors underlying its development. Here, we generated functional induced dopaminergic neurons (iDANs) that were directly reprogrammed from adult human dermal fibroblasts of patients with idiopathic Parkinsons disease to investigate diseaserelevant pathology. We show that iDANs derived from Parkinsons disease patients exhibit lower basal chaperone-mediated autophagy as compared to iDANs of healthy donors. Furthermore, stress-induced autophagy resulted in an accumulation of macroautophagic structures in induced neurons (iNs) derived from Parkinsons disease patients, independently of the specific neuronal subtype but dependent on the age of the donor. Finally, we found that these impairments in patient-derived iNs lead to an accumulation of phosphorylated alpha-synuclein, a hallmark of Parkinsons disease pathology. Taken together, our results demonstrate that direct neural reprogramming provides a patient-specific model to study aged neuronal features relevant to idiopathic Parkinsons disease.

neuroscience↗

bioRxiv2021

Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington's disease

Huntingtons disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD has remained challenging, as rodent and cellular models poorly recapitulate the disease. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. The neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites presented by HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild type HTT in neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in aged patient derived HD-neurons and provides a new rational for future development of autophagy activation therapies.

neuroscience↗