Biology subjects

Vila Bover, M.

Publications and source records attributed to Vila Bover, M..

3 recordsLinked to original sources

bioRxiv2023

Neuromelanin accumulation drives endogenous synucleinopathy in non-human primates

Although neuromelanin (NMel) is a dark pigment characteristic of dopaminergic neurons in the human substantia nigra pars compacta (SNpc), its potential role in the pathogenesis of Parkinsons disease (PD) has often been neglected since most commonly used laboratory animals lack NMel. Here we took advantage of adeno-associated viral vectors encoding the human tyrosinase gene for triggering a time-dependent NMel accumulation within SNpc dopaminergic neurons in macaques up to similar levels of pigmentation as observed in elderly humans. Furthermore, NMel accumulation induced an endogenous synucleinopathy mimicking intracellular inclusions typically observed in PD together with a progressive degeneration of NMel-expressing dopaminergic neurons. Moreover, Lewy body-like intracellular inclusions were observed in cortical areas of the frontal lobe receiving dopaminergic innervation, supporting a circuit-specific anterograde spread of endogenous synucleinopathy by permissive trans-synaptic templating. In summary, the conducted strategy resulted in the development and characterization of a new macaque model of PD matching the known neuropathology of this disorder with unprecedented accuracy. Most importantly, evidence is provided showing that intracellular aggregation of endogenous alpha-synuclein is triggered by NMel accumulation, therefore any therapeutic approach intended to decrease NMel levels may provide appealing choices for the successful implementation of novel PD therapeutics.

neuroscience↗

bioRxiv2019

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates

AO_SCPLOWBSTRACTC_SCPLOWDopaminergic neuronal cell death, associated with intracellular -synuclein (-syn)-rich protein aggregates (termed Lewy bodies), is a well-established characteristic of Parkinsons disease. Much evidence, accumulated from multiple experimental models has suggested that -syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct -syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular -syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

neuroscience↗

bioRxiv2018

Impairment of neuronal mitophagy by mutant huntingtin

Neuronal homeostasis depends on the proper functioning of different quality control systems. The accurate degradation of dysfunctional mitochondria by mitophagy is essential for maintaining mitochondrial quality and quantity in neurons. Huntingting protein (Htt) can interact with numerous other proteins and thereby perform multiple biological functions in the cell. We investigated the role of Htt during neuronal mitophagy in post-mitotic differentiated striatal neurons avoiding artificial overexpression of mitophagy-related proteins. Our study shows that Htt promotes the physical proximity of different protein complexes during initiation of the mitophagy process. Htt is needed to promote the ULK1 complex activation, the recruitment of the essential receptors of mitophagy -optineurin and NDP52- and the interaction of these receptors with LC3-II. Mutant Htt also causes a gain of toxic function avoiding the formation of the Beclin1-Vps34 initiation complex. We report that the presence of the expanded polyQ tract can affect the efficiency of neuronal mitophagy and consequently promote the accumulation of damaged mitochondria and increase oxidative stress, leading to mitochondrial dysfunction and contributing to neurodegeneration in Huntingtons disease.

neuroscience↗