Biology subjects

Gonzalez-Sepulveda, M.

Publications and source records attributed to Gonzalez-Sepulveda, M..

5 recordsLinked to original sources

bioRxiv2026

Alpha-synuclein and neuromelanin converge to promote Parkinsons disease pathology

Parkinsons disease (PD) is defined by the preferential degeneration of neuromelanin (NM)-containing dopamine-producing neurons in the substantia nigra (SN), accompanied by intraneuronal inclusions rich in alpha-synuclein (aSYN). However, the mechanistic relationship between NM accumulation and aSYN pathology remains unclear. Here, we reveal a bidirectional pathogenic relationship between aSYN and NM. In human post-mortem midbrain tissue, ventral nigral neurons with high NM content display increased aSYN mRNA expression and are preferentially lost in PD. In a rat model that recapitulates age-dependent, human-like NM accumulation via targeted tyrosinase (TYR) expression, co-expression of aSYN accelerates NM buildup, enhances aSYN oligomerization, and aggravates nigrostriatal degeneration. Mechanistically, aSYN oligomerization in NM-producing rats decreases vesicular dopamine storage and impairs vesicle fusion with the plasma membrane, increasing cytosolic dopamine availability for oxidation into NM. Together, these findings support a pathogenic feedback loop in which elevated aSYN accelerates NM synthesis through disrupted dopamine compartmentalization, while NM accumulation further promotes aSYN aggregation and neuronal loss. This aSYN-NM axis may underlie the preferential vulnerability of pigmented nigral neurons in PD and provide a mechanistic framework for the development of future targeted therapeutics.

neuroscience↗

bioRxiv2026

Age-dependent brain pigmentation drives early neuroinflammatory molecular signatures linked to neurodegeneration

BackgroundNeuromelanin (NM) is a pigment that progressively accumulates with age in catecholaminergic neurons, particularly in the substantia nigra, ventral tegmental area, and locus coeruleus. These neuronal populations are especially vulnerable to degeneration in Parkinsons disease (PD). Elevated intracellular NM levels have been linked to neurodegeneration and PD-like phenotypes in experimental models. However, the molecular mechanisms underlying NM-induced pathology remain poorly understood, as human studies cannot disentangle the specific effects of NM accumulation from those of normal aging. MethodsWe performed transcriptomic microarray analysis on laser-captured catecholaminergic neurons and regions (substantia nigra, ventral tegmental area, locus coeruleus) from NM-producing transgenic mice (tgNM) and NM-free wild-type controls across different ages, and compared them to data from postmortem human brain tissue. One of the molecular targets identified, GPNMB, was validated in mouse and human tissue, and functionally tested in vivo. ResultsWe identified region- and age-dependent transcriptional changes associated with progressive NM accumulation. NM consistently upregulated neuroinflammatory pathways with enrichment of disease-associated microglial genes, while downregulating transcription, translation, and mitochondrial functions. Locus coeruleus exhibited the earliest and strongest transcriptional alterations, whereas substantia nigra and ventral tegmental area showed a later-onset, age-progressive transcriptional dysfunction. Neuron-specific analyses revealed that many changes originated within NM-containing neurons rather than being solely glial-driven. NM-driven transcriptional profiles in mice strongly correlated with postmortem data from PD patients, underscoring their translational relevance. Among molecular targets, the glycoprotein GPNMB was consistently upregulated in NM-containing neurons and validated at RNA and protein levels in both NM-producing transgenic mice and human PD brains. Functional experiments demonstrated that GPNMB overexpression attenuated NM-linked dopaminergic neurodegeneration and improved motor performance in mice. ConclusionThis study provides a comprehensive in vivo characterization of NM-specific transcriptomic changes in catecholaminergic neurons, showing that NM accumulation drives neuroinflammatory and neurodegenerative programs. Our results support that the neuroinflammatory changes observed in tgNM mice and in human PD represent early pathological events that precede overt neurodegeneration. The disease-associated gene GPNMB emerged as a conserved NM-induced factor with protective properties, highlighting its potential as a therapeutic target in PD and aging-related neurodegeneration.

neuroscience↗

bioRxiv2024

LRRK2-mutant microglia trigger dopaminergic neurodegeneration when activated by neuromelanin

Parkinsons disease (PD) is a progressive, incurable neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons (DAn) in the substantia nigra of the midbrain. Non-neuronal cells are increasingly recognized as contributors to PD. We generated human microglia-like cells (hMG) from induced pluripotent stem cells (iPSC) derived from patients with LRRK2 PD-causing mutations, gene-corrected isogenic controls, and healthy donors. While neither genotype induced neurodegeneration in healthy DAn, LRRK2 hMG become hyperreactive to LPS stimulation, exhibiting increased cytokine expression, reactive oxygen species, and phagocytosis. When exposed to NM-containing particles, but not -synuclein fibrils, LRRK2 hMG trigger DAn degeneration, in a process that is prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, post-mortem analysis of midbrain tissue of LRRK2-PD patients show increased microglia activation around NM-containing neurons, confirming our in vitro findings. Overall, our work highlights NM-activated microglias role in PD progression, and provides a model for testing therapeutic targets.

cell biology↗

bioRxiv2023

Modelling human brain-wide pigmentation in rodents recapitulates age-related multisystem neurodegenerative deficits

One key limitation in developing effective treatments for neurodegenerative diseases is the lack of models accurately mimicking the complex physiopathology of the human disease. Humans accumulate with age the pigment neuromelanin inside neurons that synthesize catecholamines. Neurons reaching the highest neuromelanin levels preferentially degenerate in Parkinsons, Alzheimers and apparently healthy aging individuals. However, this brain pigment is not taken into consideration in current animal models because common laboratory species, such as rodents, do not produce neuromelanin. Here we generate a tissue-specific transgenic mouse, termed tgNM, that mimics the human age-dependent brain-wide distribution of neuromelanin within catecholaminergic regions, based on the constitutive catecholamine-specific expression of human melanin-producing enzyme tyrosinase. We show that, in parallel to progressive human-like neuromelanin pigmentation, these animals display age-related neuronal dysfunction and degeneration affecting numerous brain circuits and body tissues, linked to motor and non-motor deficits, reminiscent of early neurodegenerative stages. This model may open new research avenues in brain aging and neurodegeneration.

neuroscience↗

bioRxiv2022

In vivo reduction of age-dependent neuromelanin accumulation mitigates features of Parkinson's disease

Humans accumulate with age the dark-brown pigment neuromelanin inside specific neuronal groups. Neurons with the highest neuromelanin levels are particularly susceptible to degeneration in Parkinsons disease, especially dopaminergic neurons of the substantia nigra (SN), the loss of which leads to characteristic motor Parkinsons disease symptoms. In contrast to humans, neuromelanin does not appear spontaneously in most animals, including rodents, and Parkinsons disease is an exclusively human condition. Using humanized neuromelanin-producing rodents, we recently found that neuromelanin can trigger Parkinsons disease pathology when accumulated above a specific pathogenic threshold. Here, by taking advantage of this newly developed animal model, we assessed whether the intracellular buildup of neuromelanin that occurs with age can be slowed down in vivo to prevent or attenuate Parkinsons disease. Because neuromelanin derives from the oxidation of free cytosolic dopamine, we enhanced dopamine vesicular encapsulation in the SN of neuromelanin-producing rats by viral vector-mediated overexpression of vesicular monoamine transporter 2 (VMAT2). This strategy reduced the formation of potentially toxic oxidized dopamine species that can convert into neuromelanin and maintained intracellular neuromelanin levels below their pathogenic threshold. Decreased neuromelanin production was associated with an attenuation of Lewy body-like inclusion formation and a long-term preservation of dopamine homeostasis, nigrostriatal neuronal integrity and motor function in these animals. Our results demonstrate the feasibility and therapeutic potential of modulating age-dependent intracellular neuromelanin production in vivo, thereby opening an unexplored path for the treatment of Parkinsons disease and, in a broader sense, brain aging.

neuroscience↗