iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease

Woodard, Chris M.; Campos, Brian A.; Kuo, Sheng‐Han; Nirenberg, Melissa J.; Nestor, Michael W.; Zimmer, Matthew; Mosharov, Eugene V.; Sulzer, David; Zhou, Haoming; Paull, Daniel; Clark, Lorraine N.; Schadt, Eric E.; Sardi, S. Pablo; Rubin, Lee L.; Eggan, Kevin; Brock, Mathew; Lipnick, Scott; Rao, Mahendra S.; Chang, Stephen; Li, Aiqun; Noggle, Scott

doi:10.1016/j.celrep.2014.10.023

Cited by 206 publications

(194 citation statements)

References 34 publications

(47 reference statements)

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“…For example, in a new approach, genes related to the dopaminergic system were studied in iPSC neurons from twins without and with PD. Genes for the dopamine receptors and for dopamine synthesis, uptake, release, and metabolism were found to be differentially expressed in PD neurons compared to those from the identical twin (Woodard et al, 2014). MAO B was higher by almost 1.5-fold in both of the PD-affected persons compared to their unaffected twin.…”

Section: Mao Influences the Monoamine Levels In Brainmentioning

confidence: 85%

“…Later work has established that it is MAO B activity that increases with age in human brain (associated with gliosis) and is elevated in several degenerative diseases. Recently, a range of experimental techniques have been used to demonstrate increased MAO B activity in Huntington's, Alzheimer's and Parkinson's diseases (Kennedy et al, 2003, Zellner et al, 2012, Woodard et al, 2014, Ooi et al, 2015. For example, in a new approach, genes related to the dopaminergic system were studied in iPSC neurons from twins without and with PD.…”

Section: Mao Influences the Monoamine Levels In Brainmentioning

confidence: 99%

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Molecular aspects of monoamine oxidase B

Ramsay

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Graphical abstract Highlights• MAO B activity depends on both amine and oxygen concentrations KeywordsMonoamine oxidase B; kinetics; drug design; neurotransmitter levels; platelet AbbreviationsAlzheimer's Disease, AD; Parkinson's Disease, PD; dopamine transporter, DAT; serotonin transporter, SERT; noradrenaline transporter, NET; the vesicular transporter, VMAT; Gprotein coupled receptor, GPCR; induced pluripotent stem cells, iPSC; serotonin reuptake inhibitor, SSRI; brain-derived neurotrophic factor, BDNF; multi-target designed ligands, MTDL; IC 50 , the concentration of compound required to inhibit a specified assay by 50%; K i , a kinetically measured inhibitor dissociation constant. Word count -approx 5490 (excluding references). Abstract 196 words.3

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Section: Mao Influences the Monoamine Levels In Brainmentioning

confidence: 85%

Section: Mao Influences the Monoamine Levels In Brainmentioning

confidence: 99%

Molecular aspects of monoamine oxidase B

Ramsay

2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…For example, changes in the composition of sphingolipids have been reported to stabilize soluble oligomeric forms of isolated recombinant α-synuclein (13). Endogenously produced α-synuclein can also accumulate in induced pluripotent (iPS) cells from patients with PD who harbor homozygous or heterozygous GBA mutations, presumably because of the presence of increased levels of membrane glycosphingolipids (12,13,40). It appears reasonable, then, that persistent reduction in brain glycosphingolipids of the synucleinopathy animal slowed the accumulation of aggregated proteins (ubiquitin, α-synuclein, and tau), indicating the potential for the orally available brain-penetrant GCS inhibitor to modify disease progression in patients with PD carrying GBA mutations.…”

Section: Discussionmentioning

confidence: 99%

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Sardi

Viel

Clarke

et al. 2017

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

167

158

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Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba D409V/D409V and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment of Gba D409V/D409V mice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment of A53T-SNCA mice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a diseasemodifying therapeutic strategy for GBA-related synucleinopathies and conceivably for certain forms of sporadic disease.Parkinson's disease | GBA mutations | glucosylceramide synthase | Gaucher disease | Lewy body dementia

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“…These iPSCs can then be differentiated into especially disease-relevant cell types, such as dopaminergic neurons [28][29][30]. This allows for the characterisation of human dopaminergic neurons carrying GBA mutations.…”

Section: Models Of Gba-pdmentioning

confidence: 99%

Glucocerebrosidase Mutations in Parkinson Disease

O’Regan

deSouza

Balestrino

et al. 2017

JPD

100

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Abstract.Following the discovery of a higher than expected incidence of Parkinson Disease (PD) in Gaucher disease, a lysosomal storage disorder, mutations in the glucocerebrocidase (GBA) gene, which encodes a lysosomal enzyme involved in sphingolipid degradation were explored in the context of idiopathic PD. GBA mutations are now known to be the single largest risk factor for development of idiopathic PD. Clinically, on imaging and pharmacologically, GBA PD is almost identical to idiopathic PD, other than certain features that can be identified in the specialist research setting but not in routine clinical practice. In patients with a known GBA mutation, it is possible to monitor for prodromal signs of PD. The clinical similarity with idiopathic PD and the chance to identify PD at a pre-clinical stage provides a unique opportunity to research therapeutic options for early PD, before major irreversible neurodegeneration occurs. However, to date, the molecular mechanisms which lead to this increased PD risk in GBA mutation carriers are not fully elucidated. Experimental models to define the molecular mechanisms and test therapeutic options include cell culture, transgenic mice and other in vivo models amenable to genetic manipulation, such as drosophilia. Some key pathological pathways of interest in the context of GBA mutations include alpha synuclein aggregation, lysosomal-autophagy axis changes and endoplasmic reticulum stress. Therapeutic agents that exploit these pathways are being developed and include the small molecule chaperone Ambroxol. This review aims to summarise the main features of GBA-PD and provide insights into the pathological relevance of GBA mutations on molecular pathways and the therapeutic implications for PD resulting from investigation of the role of GBA in PD.

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iPSC-Derived Dopamine Neurons Reveal Differences between Monozygotic Twins Discordant for Parkinson’s Disease

Cited by 206 publications

References 34 publications

Molecular aspects of monoamine oxidase B

Molecular aspects of monoamine oxidase B

Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models

Glucocerebrosidase Mutations in Parkinson Disease

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