Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease

Cooper, Oliver; Seo, Hyemyung; Andrabi, Shaida A.; Guardia‐Laguarta, Cristina; Graziotto, John J.; Sundberg, Maria; McLean, Jesse R.; Carrillo-Reid, Luis; Xie, Zhong; Osborn, Teresia; Hargus, Gunnar; Deleidi, Michela; Lawson, T.; Bogetofte, Helle; Pérez-Torres, Eduardo; Clark, Lorraine N.; Moskowitz, Carol; Mazzulli, Joseph R.; Chen, Li; Volpicelli‐Daley, Laura A.; Romero, Norma B.; Jiang, Houbo; Uitti, Ryan J.; Huang, Zhi; Opala, Grzegorz; Scarffe, Leslie A.; Dawson, Valina L.; Klein, Christine; Feng, Jian; Ross, Owen A.; Trojanowski, John Q.; Lee, Virginia M.‐Y.; Marder, Karen; Surmeier, D. James; Wszołek, Zbigniew K.; Przedborski, Serge; Krainc, Dimitri; Dawson, Ted M.; Isacson, Ole

doi:10.1126/scitranslmed.3003985

Cited by 460 publications

(443 citation statements)

References 72 publications

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“…Similar observations were made in a third study done by Cooper and colleagues in 2012 in which human iPSCs were again derived from patients with the Q456X PINK1 mutation [253]. Supplementary results to validate the cellular model confirmed that the PINK1 mutant iPSCs are able to differentiate into all the neuronal lineages including DA neurons and display normal karyotyping.…”

Section: Pink1 (Park6)supporting

confidence: 80%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, nonmotor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/bcatenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PDrelated genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

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Section: Pink1 (Park6)supporting

confidence: 80%

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Grand

Gonzalez-Cano

Pavlou

et al. 2014

Cell. Mol. Life Sci.

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“…To reach that goal, it seems essential to provide energy levels close to those observed in healthy human brains, especially because several neurological disorders have been shown to be related to mitochondria dysfunctions (41)(42)(43). The mammalian brain uses glucose as one of its main sources of energy (44).…”

Section: Brainphys Basal Medium Better Mimics the Human Brain's Energymentioning

confidence: 99%

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

Bardy

Hurk

Eames

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

335

363

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Human cell reprogramming technologies offer access to live human neurons from patients and provide a new alternative for modeling neurological disorders in vitro. Neural electrical activity is the essence of nervous system function in vivo. Therefore, we examined neuronal activity in media widely used to culture neurons. We found that classic basal media, as well as serum, impair action potential generation and synaptic communication. To overcome this problem, we designed a new neuronal medium (BrainPhys basal + serum-free supplements) in which we adjusted the concentrations of inorganic salts, neuroactive amino acids, and energetic substrates. We then tested that this medium adequately supports neuronal activity and survival of human neurons in culture. Long-term exposure to this physiological medium also improved the proportion of neurons that were synaptically active. The medium was designed to culture human neurons but also proved adequate for rodent neurons. The improvement in BrainPhys basal medium to support neurophysiological activity is an important step toward reducing the gap between brain physiological conditions in vivo and neuronal models in vitro.

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“…Dopamine neurons derived from pluripotent stem cells from R1441C mutation carriers revealed mitochondrial pathology presumably due to mitochondrial DNA damage, which could be rescued pharmacologically or by gene correction [153,154]. Similar effects on mitochondrial function have been seen in G2019S fibroblasts [155].…”

Section: Effects Of Lrrk2 On Cellular Phenotypes and Physiologymentioning

confidence: 61%

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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Pharmacological Rescue of Mitochondrial Deficits in iPSC-Derived Neural Cells from Patients with Familial Parkinson’s Disease

Cited by 460 publications

References 72 publications

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Neural stem cells in Parkinson’s disease: a role for neurogenesis defects in onset and progression

Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

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