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Martínez Menárguez, José Ángel

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Martínez Menárguez, José Ángel
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Universidad de Murcia. Departamento de Biología Celular e Histología
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    Fragmentation of the Golgi complex of dopaminergic neurons in human substantia nigra: new cytopathological findings in Parkinson's disease
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2021) Tomás, Mónica; Martínez Martínez, Narcisa; Cara Esteban, Mireia; Martínez Alonso, Emma; Martínez Menárguez, José Ángel
    Fragmentation of the Golgi ribbon is a common feature of Parkinson's disease and other neurodegenerative diseases. This alteration could be the consequence of the anterograde and retrograde transport imbalance, α-synuclein aggregates, and/or cytoskeleton alterations. Most information on this process has been obtained from cellular and animal experimental models, and as such, there is little information available on human tissue. If the information on human tissue was available, it may help to understand the cytopathological mechanisms of this disease. In the present study, we analyzed the morphological characteristics of the Golgi complex of dopaminergic neurons in human samples of substantia nigra of control and Parkinson's disease patients. We measured the expression levels of putative molecules involved in Golgi fragmentation, including α-synuclein, tubulin, and Golgi-associated regulatory and structural proteins. We show that, as a consequence of the disease, the Golgi complex is fragmented into small stacks without vesiculation. We found that only a limited number of regulatory proteins are altered. Rab1, a small GTPase regulating endoplasmic reticulum-to-Golgi transport, is the most dramatically affected, being highly overexpressed in the surviving neurons. We found that the SNARE protein syntaxin 5 forms extracellular aggregates resembling the amyloid plaques characteristic of Alzheimer's disease. These findings may help to understand the cytopathology of Parkinson's disease.
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    Low temperature (15ºC) induces COPII dissociation from membranes and slow exit from the endoplasmic reticulum in HeLa cells
    (Springer, 2007-08-11) Tomás, Mónica; Ballesta Germán, José; Martínez Alonso, Emma; Martínez Menárguez, José Ángel; Biología Celular e Histología
    Low temperature induces a transport blockade at the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) in cultured cells. Our previous studies support that the primary effect of low temperature is the detachment of COPI complexes from membranes. In the present study, we have used immunofluorescence and cryoimmunoelectron microscopy to investigate the effects of low temperature on both COPII and clathrin coat complexes in HeLa cells. Strikingly, COPII proteins moved from membranes to the cytosol at 15ºC, accumulating into electron-dense areas. In agreement with this observation, we also showed that ER exit is delayed in cells cultured at this temperature. By contrast, clathrin coat is not affected. Together, our results demonstrate that low temperature induces COPII dissociation from membranes and slow exit from the endoplasmic reticulum.
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    Structure and Dynamics of the Golgi Complex at 15ºC: Low Temperature Induces the Formation of Golgi-Derived Tubules
    (Wiley, 2005-01) Egea, Gustavo; Ballesta Germán, José; Martínez Alonso, Emma; Martínez Menárguez, José Ángel; Biología Celular e Histología
    Immunofluorescence and cryoimmunoelectron microscopy were used to examine the morphological and functional effects on the Golgi complex when protein transport is blocked at the ERGIC (ER-Golgi intermediate compartment) in HeLa cells incubated at low temperature (15ºC). At this temperature, the Golgi complex showed long tubules containing resident glycosylation enzymes but not matrix proteins. These Golgi-derived tubules also lacked anterograde (VSV-G) or retrograde (Shiga toxin) cargo. The formation of tubules was dependent on both energy and intact microtubule and actin cytoskeletons. Conversely, brefeldin A or cycloheximide treatments did not modify the appearance. When examined at the electron microscope, Golgi stacks were long and curved and appeared connected to tubules immunoreactive to galactosyltransferase antibodies but devoid of Golgi matrix proteins. Strikingly, COPI proteins moved from membranes to the cytosol at 15ºC which could explain the formation of tubules.
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    The Golgi complex of dopaminergic enteric neurons is fragmented in a hemiparkinsonian rat model
    (Wiley, 2023-10-19) Mireia Cara-Esteban; María Pilar Marín; Martínez Alonso, Emma; Sergio Martínez-Bellver; Vicent Teruel-Martí; Martínez Menárguez, José Ángel; Mónica Tomás; Biología Celular e Histología; Facultad de Medicina
    Since gastrointestinal disorders are early consequences of Parkinson's disease (PD), this disease is clearly not restricted to the central nervous system (CNS), but also significantly affects the enteric nervous system (ENS). Large aggregates of the protein α-synuclein forming Lewy bodies, the prototypical cytopathological marker of this disease, have been observed in enteric nervous plexuses. However, their value in early prognosis is controversial. The Golgi complex (GC) of nigral neurons appears fragmented in Parkinson's disease, a characteristic common in most neurodegenerative diseases. In addition, the distribution and levels of regulatory proteins such as Rabs and SNAREs are altered, suggesting that PD is a membrane traffic-related pathology. Whether the GC of enteric dopaminergic neurons is affected by the disease has not yet been analyzed. In the present study, dopaminergic neurons in colon nervous plexuses behave as nigral neurons in a hemiparkinsonian rat model based on the injection of the toxin 6-OHDA. Their GCs are fragmented, and some regulatory proteins' distribution and expression levels are altered. The putative mechanisms of the transmission of the neurotoxin to the ENS are discussed. Our results support the possibility that GC structure and the level of some proteins, especially syntaxin 5, could be helpful as early indicators of the disease. Research Highlights: The Golgi complexes of enteric dopaminergic neurons appear fragmented in a Parkinson's disease rat model. Our results support the hypothesis that the Golgi complex structure and levels of Rab1 and syntaxin 5 could be helpful as early indicators of the disease.
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    Focus on the Small GTPase Rab1: a key player in the pathogenesis of parkinson’s disease
    (MDPI, 2021-11-08) Martínez Menárguez, José Ángel; Martínez Alonso, Emma; Cara-Esteban, Mireia; Tomás, Mónica; Biología Celular e Histología; Facultad de Medicina
    Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra and the formation of large aggregates in the survival neurons called Lewy bodies, which mainly contain α-synuclein (α-syn). The cause of cell death is not known but could be due to mitochondrial dysfunction, protein homeostasis failure, and alterations in the secretory/endolysosomal/autophagic pathways. Survival nigral neurons overexpress the small GTPase Rab1. This protein is considered a housekeeping Rab that is necessary to support the secretory pathway, the maintenance of the Golgi complex structure, and the regulation of macroautophagy from yeast to humans. It is also involved in signaling, carcinogenesis, and infection for some pathogens. It has been shown that it is directly linked to the pathogenesis of PD and other neurodegenerative diseases. It has a protective effect against α–σψν toxicity and has recently been shown to be a substrate of LRRK2, which is the most common cause of familial PD and the risk of sporadic disease. In this review, we analyze the key aspects of Rab1 function in dopamine neurons and its implications in PD neurodegeneration/restauration. The results of the current and former research support the notion that this GTPase is a good candidate for therapeutic strategies. View Full-Text
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