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1.
Stem Cell Reports ; 18(5): 1090-1106, 2023 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-37163979

RESUMO

Mitochondrial dysfunction involving mitochondria-associated ER membrane (MAM) dysregulation is implicated in the pathogenesis of late-onset neurodegenerative diseases, but understanding is limited for rare early-onset conditions. Loss of the MAM-resident protein WFS1 causes Wolfram syndrome (WS), a rare early-onset neurodegenerative disease that has been linked to mitochondrial abnormalities. Here we demonstrate mitochondrial dysfunction in human induced pluripotent stem cell-derived neuronal cells of WS patients. VDAC1 is identified to interact with WFS1, whereas loss of this interaction in WS cells could compromise mitochondrial function. Restoring WFS1 levels in WS cells reinstates WFS1-VDAC1 interaction, which correlates with an increase in MAMs and mitochondrial network that could positively affect mitochondrial function. Genetic rescue by WFS1 overexpression or pharmacological agents modulating mitochondrial function improves the viability and bioenergetics of WS neurons. Our data implicate a role of WFS1 in regulating mitochondrial functionality and highlight a therapeutic intervention for WS and related rare diseases with mitochondrial defects.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Síndrome de Wolfram , Humanos , Síndrome de Wolfram/genética , Síndrome de Wolfram/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Mitocôndrias/metabolismo , Mutação
2.
Psychopharmacology (Berl) ; 238(9): 2569-2585, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34089344

RESUMO

Neuropsychiatric disorders are multifactorial disturbances that encompass several hypotheses, including changes in neurodevelopment. It is known that brain development disturbances during early life can predict psychosis in adulthood. As we have previously demonstrated, rotenone, a mitochondrial complex I inhibitor, could induce psychiatric-like behavior in 60-day-old rats after intraperitoneal injections from the 5th to the 11th postnatal day. Because mitochondrial deregulation is related to psychiatric disorders and the establishment of animal models is a high-value preclinical tool, we investigated the responsiveness of the rotenone (Rot)-treated newborn rats to pharmacological agents used in clinical practice, haloperidol (Hal), and methylphenidate (MPD). Taken together, our data show that Rot-treated animals exhibit hyperlocomotion, decreased social interaction, and diminished contextual fear conditioning response at P60, consistent with positive, negative, and cognitive deficits of schizophrenia (SZ), respectively, that were reverted by Hal, but not MPD. Rot-treated rodents also display a prodromal-related phenotype at P35. Overall, our results seem to present a new SZ animal model as a consequence of mitochondrial inhibition during a critical neurodevelopmental period. Therefore, our study is crucial not only to elucidate the relevance of mitochondrial function in the etiology of SZ but also to fulfill the need for new and trustworthy experimentation models and, likewise, provide possibilities to new therapeutic avenues for this burdensome disorder.


Assuntos
Haloperidol/uso terapêutico , Esquizofrenia , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Fenótipo , Ratos , Rotenona , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico
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