Browsing by Author "Grunenwald, Felipe"

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    IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson’s disease models
    (2023) Arcos, Javiera; Grunenwald, Felipe; Sepúlveda, Denisse; Jerez, Carolina; Urbina, Valentina; Huerta, Tomas; Troncoso-Escudero, Paulina; Tirado, Daniel; Pérez, Angela; Díaz-Espinoza, Rodrigo; Nova, Esteban; Kubitscheck, Ulrich; Rodríguez-Gatica, Juan Eduardo; Hertz, Claudio; Toledo, Jorge; Ahumada, Pablo; Rojas-Rivera, Diego; Martín-Montañez, Elisa; García-Fernández, María; Vidal, René L.
    Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein. We previously reported insulin-like growth factor 2 (IGF2) as a key protein downregulated in PD patients. Here we demonstrated that IGF2 treatment or IGF2 overexpression reduced the α-syn aggregates and their toxicity by IGF2 receptor (IGF2R) activation in cellular PD models. Also, we observed IGF2 and its interaction with IGF2R enhance the α-syn secretion. To determine the possible IGF2 neuroprotective effect in vivo we used a gene therapy approach in an idiopathic PD model based on α-syn preformed fibrils intracerebral injection. IGF2 gene therapy revealed a significantly preventing of motor impairment in idiopathic PD model. Moreover, IGF2 expression prevents dopaminergic neuronal loss in the SN together with a decrease in α-syn accumulation (phospho-α-syn levels) in the striatum and SN brain region. Furthermore, the IGF2 neuroprotective effect was associated with the prevention of synaptic spines loss in dopaminergic neurons in vivo. The possible mechanism of IGF2 in cell survival effect could be associated with the decrease of the intracellular accumulation of α-syn and the improvement of dopaminergic synaptic function. Our results identify to IGF2 as a relevant factor for the prevention of α-syn toxicity in both in vitro and preclinical PD models.
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    Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease
    (2022) Espinoza, Sandra; Grunenwald, Felipe; Gomez, Wileidy; García, Felipe; Abarzúa, Lorena; Oyarce, Sebastián; Hernández, María; Cortés, Bastián; Uhrig, Markus; Ponce, Daniela; Durán, Claudia; Hetz, Claudio; SanMartín, Carol; Cornejo, Victor; Ezquer, Fernando; Parra, Valentina; Behrens, María; Manque, Patricio; Rojas, Diego; Vidal, René; Woehlbier, Ute; Nassif, Melissa
    Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically

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