Biology subjects

Zecca, L.

Publications and source records attributed to Zecca, L..

4 recordsLinked to original sources

bioRxiv2025

Multiomic profiling reveals aberrant immunomodulatory signature in β-propeller protein-associated neurodegeneration patient iPSC-derived microglia

Microglia are the primary immune cells of the central nervous system and play a crucial role in maintaining brain homeostasis. In common neurodegenerative diseases such as Alzheimers disease and Parkinsons disease (PD), early and sustained microglial activation has been shown to precede neuronal loss, with elevated levels of microglia-derived inflammatory mediators detected in affected brain regions. In contrast, little is known about the role of microglia in rare neurodegenerative disorders. One such disorder is {beta}-propeller protein-associated neurodegeneration (BPAN), a common subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN shares pathological features with PD, including iron accumulation and selective loss of dopaminergic neurons in the substantia nigra, and is caused by mutations in the WD repeat domain 45 (WDR45) gene encoding an autophagy protein also called WIPI4. However, the pathological role of mutant WDR45 in BPAN and the possible contribution of microglia remain unresolved. We generated the first BPAN patient microglia model system using induced pluripotent stem cells (iPSCs) to identify immune-related alterations and immunomodulatory signaling changes in a disease-relevant context. Integrated transcriptomic and proteomic profiling of iPSC-derived microglia from BPAN patients revealed a consistent shift from a homeostatic to a reactive, disease-associated state. Transcriptomic analysis showed disruption of core microglial pathways, including immune activation, stress response, and autophagy, consistent with a chronic pro-inflammatory phenotype. Complementary secretome analysis identified impaired lysosomal function and increased antigen presentation pathways, further supporting persistent microglial activation. Together this suggests that dysfunctional microglial states may contribute to BPAN pathogenesis. Our findings lay the groundwork for advancing immunomodulatory research in BPAN and may open new avenues for therapeutic development targeting microglial dysfunction.

neuroscience↗

bioRxiv2023

Synthetic neuromelanin as a trigger of inflammation in the brain, new mouse model of Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative disease that is an increasing threat to an aging society. The idiopathic form of PD accounts for over 90% of all cases, and the current etiology is still unknown. One of the reasons hindering research on this form of PD is the lack of an appropriate animal models. Among mouse models of the disease, those based on the administration of neurotoxins such as 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) to the substantia nigra pars compacta (SNpc) or striatum are predominantly used. In these models, there are metabolic disturbances causing oxidative stress in the SNpc or striatum, which ultimately leads to the death of dopaminergic neurons. However, the models used so far have serious limitations, most of all they do not fully reflect the processes occurring in the course of the disease and do not consider the involvement of inflammation in the etiology and pathogenesis of PD. In this study we show that the administration of synthetic neuromelanin, which activates astrocytes and microglia, induces the inflammation and may be involved in degeneration of dopaminergic neurons. Neuromelanin under physiological conditions acts as a neuroprotector, however, released from dying dopaminergic neurons is an important factor activating astrocytes, microglia and causing neuroinflammation. Since one of the causes of Parkinsons appear to be the death of dopaminergic neurons overloaded with neuromelanin and consequent pathological activation of microglia, the use of synthetic neuromelanin reflect the natural pathological processes occurring during the development of the disease.

neuroscience↗

bioRxiv2020

Age-Associated Insolubility of Parkin in Human Midbrain is Linked to Redox Balance and Sequestration of Reactive Dopamine Metabolites

The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions, which are reflected in its posttranslational modifications. We found that in human control brain, including the S. nigra, parkin is largely insoluble after age 40 years, which is linked to its oxidation, e.g., at Cys95 and Cys253. In mice, oxidative stress increases posttranslational modifications at parkin cysteines and reduces its solubility. Oxidation of recombinant parkin also promotes insolubility and aggregate formation, but in parallel, lowers hydrogen peroxide (H2O2). This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. Intriguingly, in parkin-deficient human brain H2O2 concentrations are elevated. In prkn-null mice, H2O2 levels are dysregulated under oxidative stress conditions, such as acutely by MPTP-toxin exposure or chronically due to a second genetic hit. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic M17 cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at primate-specific Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation. In sections of normal, adult human midbrain, parkin specifically co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these redox effects may augment oxidative stress in dopamine producing neurons of mutant PRKN allele carriers, thereby contributing to neurodegeneration.

neuroscience↗

bioRxiv2020

Parkinson Disease-Linked Parkin Mediates Redox Reactions That Lower Oxidative Stress In Mammalian Brain

We recently hypothesized that parkin plays a role in redox homeostasis and provided evidence that it directly reduces hydrogen peroxide (H2O2) in vitro. Here, we examined this anti-oxidant activity in vivo. Informed by findings in human brain, we demonstrate that elevated oxidative stress promotes parkin insolubility in mice. In normal mouse brain parkin was partially oxidized, e.g., at cysteines 195 and 252, which was augmented by oxidative stress. Although under basal conditions H2O2 levels were unchanged in adult prkn-/- brain, a parkin-dependent reduction of cytosolic H2O2 was observed when mitochondria were impaired, either due to neurotoxicant exposure (MPTP) or Sod2 haploinsufficiency. In accordance, markers of oxidative stress, e.g., protein carbonylation and nitrotyrosination, were elevated in the cytosol but not in mitochondria from prkn-/- mice. Nevertheless, this rise in oxidative stress led to changes in mitochondrial enzyme activities and the metabolism of glutathione in cells and mammalian brain. In parkins absence reduced glutathione concentrations were increased including in human cortex. This compensation was not due to new glutathione synthesis but attributed to elevated oxidized glutathione (GSSG)-reductase activity. Moreover, we discovered that parkin also recycled GSSG to its reduced form. With this reaction, parkin became S-glutathionylated, e.g., at cysteines 59 and human-specific 95. This oxidative modification was reversed by glutaredoxin. Our results demonstrate that cytosolic parkin mediates anti-oxidant reactions including H2O2 reduction and glutathione regeneration. These reducing activities lead to a range of oxidative modifications in parkin itself. In parkin-deficient brain oxidative stress rises despite changes to maintain redox balance.

neuroscience↗