Biology subjects

Obeso, J. A.

Publications and source records attributed to Obeso, J. A..

3 recordsLinked to original sources

bioRxiv2026

Tier-specific location of Lewy body pathology and related neuromelanin levels drive dopaminergic cell vulnerability in pigmented non-human primates

Although a differential vulnerability of dopaminergic neurons to degeneration based on their specific location within the dorsal and ventral tiers of the substantia nigra pars compacta (SNcD and SNcV, respectively) has long been postulated, the underlying mechanisms sustaining these tier-specific differences remain poorly understood. Here, upon inducing a viral-mediated enhancement of neuromelanin (NMel) accumulation within dopaminergic neurons in non-human primates, the distribution of Lewy body-like inclusions (LBs) was analyzed within identified SNcD and SNcV neurons, together with their intracellular NMel levels. Results showed that the vast majority of intracytoplasmic inclusions were found in SNcV neurons, and indeed correlated to higher pigmentation levels. By contrast, only very few LBs were found in calbindin-positive neurons of the SNcD, which in parallel exhibited very low levels of NMel accumulation. These results postulate an additive effect made of a tier-specific location of LB burden together with high pigmentation levels as synergistic drivers sustaining the preferential vulnerability of SNcV dopaminergic neurons. Moreover, the evidence obtained here supported that NMel accumulation beyond a given threshold triggers the aggregation of endogenous -Syn in the form of LBs; therefore, approaches intended to reduce pigmentation levels in SNcV neurons would likely induce a neuroprotective effect by preventing the subsequent aggregation of -Syn.

neuroscience↗

bioRxiv2024

Specific proteolysis mediated by a p97-directed proteolysis-targeting chimera (PROTAC)

The p97 protein is a member of the AAA + family of ATPases. It is a mechanoenzyme that uses energy from ATP hydrolysis to promote protein unfolding and segregation actively. The unfolded products of p97 are presented to the 26S Proteasome for degradation. p97 substrate recognition is mediated by adaptors, which interact with substrates directly or indirectly through ubiquitin modifications, resulting in substrate funnelling into the central pore of the p97 hexamer and unfolding. We have engineered synthetic adaptors to target specific substrates to p97, using the extraordinary intracellular binding capabilities of camelid nanobodies fused to the UBX domain of the p97 Adapter FAF1. In such a way, we created a p97-directed proteolysis-targeting chimera (PROTAC), representing a unique E3 ubiquitin ligase-independent strategy to promote specific proteolysis.

biochemistry↗

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↗