Biology subjects

Laguna, A.

Publications and source records attributed to Laguna, A..

6 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↗

bioRxiv2023

Non-ablative disease-modifying effects of magnetic resonance-guided focused ultrasound in neuromelanin-producing parkinsonian rodents

Age-dependent accumulation of the brain pigment neuromelanin has been implicated in the pathogenesis of Parkinsons disease (PD). In humans, intracellular and extracellular neuromelanin levels are increased in PD postmortem brains and boosting neuromelanin production in rodents compromises neuronal function and viability and triggers a PD-like phenotype. Focused ultrasound has been shown to reduce ultraviolet light-induced skin hyperpigmentation in guinea pig and to remove brain extracellular {beta}-amyloid plaques in Alzheimers mouse models. Here we show that repeated application of transcranial focused ultrasound (tFUS) is able to decrease intracellular and extracellular neuromelanin levels in neuromelanin-producing parkinsonian rats, compared to sham-treated animals, without the need for any additional therapeutic agent or intervention. Reduced neuromelanin levels in tFUS-treated animals were associated with decreased Lewy-like pathology, preserved dopaminergic phenotype, attenuated nigrostriatal degeneration, reduced glial activation, and long-term recovery of motor function. Our findings indicate that tFUS treatment applied at prodromal/early disease stages provides by itself extended structural and functional preservation of the nigrostriatal pathway in neuromelanin-producing parkinsonian rats without causing overt neuronal damage. This FDA-approved technology should thus be explored further as a noninvasive method with neuroprotective potential in PD and to maintain neuromelanin to levels below its pathogenic threshold within the aging population. One Sentence SummaryTranscranial focused ultrasound reduces age-dependent neuromelanin accumulation and provides therapeutic benefit in parkinsonian rats

neuroscience↗

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↗

bioRxiv2021

Cortical Spheroid Model for Studying the Effects of Ischemic Brain Injury

Stroke is a devastating neurological disorder and a leading cause of death and long-term disability. Despite many decades of research, there are still very few therapeutic options for patients suffering from stroke or its consequences. This is partially due to the limitations of current research models, including traditional in vitro models which lack the three-dimensional (3D) architecture and cellular make-up of the in vivo brain. 3D spheroids derived from primary postnatal rat cortex provide an in vivo-relevant model containing a similar cellular composition to the native cortex and a cell-synthesized extracellular matrix. These spheroids are costeffective, highly reproducible, and can be produced in a high-throughput manner, making this model an ideal candidate for screening potential therapeutics. To study the cellular and molecular mechanisms of stroke in this model, spheroids were deprived of glucose, oxygen, or both oxygen and glucose for 24 hours. Both oxygen and oxygen-glucose deprived spheroids demonstrated many of the hallmarks of stroke, including a decrease in metabolism, an increase in neural dysfunction, and an increase in reactive astrocytes. Pretreatment of spheroids with the antioxidant agent N-acetylcysteine (NAC) mitigated the decrease in ATP seen after 24 hours of oxygen-glucose deprivation. Together, these results show the utility of our 3D cortical spheroid model for studying ischemic injury and its potential for screening stroke therapeutics. Significance StatementThose who survive after suffering a stroke often have long-term cognitive or physical disabilities. There is currently only one available therapeutic, tissue plasminogen activator (tPA), and it must be administered within a few hours after the onset of stroke. As stroke prevalence increases with our aging population, there is a growing need for therapies to mitigate or reverse the resulting brain damage. Three-dimensional (3D) culture systems have the potential to screen novel therapeutics more reliably than traditional in vitro models. Here we present a novel 3D cortical spheroid ischemia model which replicates many of the characteristics of stroke and has the potential to be an effective tool in therapeutic development.

neuroscience↗