Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson’s disease

Drouin‐Ouellet, Janelle; Legault, Emilie M.; Nilsson, Fredrik; Pircs, Karolina; Bouquety, Julie; Petit, François; Shrigley, Shelby; Birtele, Marcella; Pereira, Maria; Storm, Petter; Sharma, Yogita; Bruzelius, Andreas; Vuono, Romina; Kele, Malin; Stoker, Thomas B; Ottosson, Daniella Rylander; Falk, Anna; Jakobsson, Johan; Barker, Roger A.; Parmar, Malin

doi:10.1016/j.stemcr.2022.08.010

Cited by 25 publications

(29 citation statements)

References 42 publications

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“…The efficiency of DA neuron induction in vitro with these modified protocols has been shown to be similar across different cell lines of different genetic backgrounds including those carrying mutations in genes associated with PD such as the SNCA triplication (α-synuclein triplication) cell liner. When iPSC-derived DA neurons from PD-affected individuals are probed further, independent of genetic cause, they have been shown to display cardinal features of neurodegeneration including formation of α-synuclein aggregates, dysregulation of neurotransmission, and increased susceptibility of DA neurons, relative to non-DA neurons, to diverse neurotoxins as indicated by cell death and overexpression of markers of oxidative stress, culminating in cell death ( Byers et al, 2011 ; Nguyen et al, 2011 ; Baena-Montes et al, 2021 ; Diao et al, 2021 ; Fukusumi et al, 2021 ; Lin et al, 2021 ; Drouin-Ouellet et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of DOT1L inhibitor in a screen for factors that promote dopaminergic neuron survival

Cui

Carey

Pera

2022

Front. Aging Neurosci.

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Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra region of the midbrain. Diagnostic criteria for PD require that at least two of three motor signs are observed: tremor, rigidity, and/or bradykinesia. The most common and effective treatment for PD is Levodopa (L-DOPA) which is readily converted to DA and has been the primary treatment since the 1960’s. Dopamine agonists have also been developed but are less effective than L-DOPA. Although the lack of a model system to study PD has hampered efforts to identify treatments, diverse screening strategies have been proposed for identification of new pharmaceutical candidates. Here, we describe a pilot screen to identify candidate molecules from a bioactive compound library, that might increase formation, maintenance and/or survival of DA neurons in vitro. The screen used a previously characterized reporter construct consisting of the luciferase gene inserted downstream of the endogenous tyrosine hydroxylase (TH) gene and neurons differentiated from human pluripotent stem cells for 18 days. The reporter mimics expression of TH and includes a secreted luciferase whose activity can be measured non-invasively over multiple timepoints. Screening of the bioactive compound library resulted in the identification of a single molecule, SGC0946, that is an inhibitor of DOT1L (Disruptor Of Telomeric silencing 1-Like) which encodes a widely-conserved histone H3K79 methyltransferase that is able to both activate and repress gene transcription. Our results indicate that SGC0946 increased reporter luciferase activity with a single treatment for 48-h post-plating being equivalent to continuous treatment. Moreover, data suggested that the total number of neurons differentiated in the assays was comparable from experiment to experiment under different SGC0946 treatments over time. In contrast, data suggested that the survival and/or maintenance of DA neurons might be specifically enhanced by SGC0946 treatment. These results document the feasibility of a set of tools for further exploration of small molecules that may impact DA neuron differentiation, maintenance and/or survival. Results provide evidence in support of other reports that indicate inhibition of DOT1L may play an important role in maintenance and survival of neural progenitor cells (NPCs) and their lineage-specific differentiation.

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Section: Discussionmentioning

confidence: 99%

Identification of DOT1L inhibitor in a screen for factors that promote dopaminergic neuron survival

Cui

Carey

Pera

2022

Front. Aging Neurosci.

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“…PD patient-derived human iNPCs of Kim’s group also have been used to evaluate the therapeutic efficacy of cryptotanshinone ( Lee et al, 2020 ), a drug that was already reported to prevent oxidative stress injury in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse PD models ( Yun et al, 2018 ). More recently, a breakthrough was made by Drouin-Ouellet et al, who generated functional iDANs from patients with idiopathic PD, showing specific age and PD-related impairments ( Drouin-Ouellet et al, 2022 ).…”

Section: Impact Of Aging Signatures In Brain Disease Modelsmentioning

confidence: 99%

“…To assess how the age-associated properties of the human donors affect PD-related pathology, the Drouin-Ouellet’s group asked whether the accumulation of lysosomal structures in healthy and PD-iNs was associated with the age of the donor ( Drouin-Ouellet et al, 2022 ). In fact, they found a positive correlation between the age and the accumulation of lysosomes in neurites and a tendency toward a positive correlation of the accumulation with age of onset at diagnosis.…”

Section: Impact Of Aging Signatures In Brain Disease Modelsmentioning

confidence: 99%

“…Directly induced neurons appear the most suitable strategy to model late-onset NDDs. Retaining all the main aging hallmarks of primary fibroblasts, iNs have proven to recapitulate age-related features in PD models ( Lee et al, 2019 , 2020 ; Drouin-Ouellet et al, 2022 ), ALS ( Liu et al, 2016 ), and HD ( Liu et al, 2014b ; Victor et al, 2018 ; Monk et al, 2021 ; Pircs et al, 2022 ).…”

Section: Current Achievements and Prospectsmentioning

confidence: 99%

“…Direct conversion approach can be used from patients’ fibroblasts ( Victor et al, 2018 ; Capano et al, 2022 ; Drouin-Ouellet et al, 2022 ; Pircs et al, 2022 ) and some evidence demonstrates that cells from all ages can be converted into iNs ( Mertens et al, 2015 ). Noteworthy, a general difficulty in reaching equal conversion rates from adult or aged fibroblasts has been reported ( Caiazzo et al, 2011 ; He et al, 2019 ), finally limiting the applicability of direct reprogramming for studying aging contribution in neurodegeneration.…”

Section: Current Achievements and Prospectsmentioning

confidence: 99%

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Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

Aversano

Caiazza

Caiazzo

2022

Front. Aging Neurosci.

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Many diseases of the central nervous system are age-associated and do not directly result from genetic mutations. These include late-onset neurodegenerative diseases (NDDs), which represent a challenge for biomedical research and drug development due to the impossibility to access to viable human brain specimens. Advancements in reprogramming technologies have allowed to obtain neurons from induced pluripotent stem cells (iPSCs) or directly from somatic cells (iNs), leading to the generation of better models to understand the molecular mechanisms and design of new drugs. Nevertheless, iPSC technology faces some limitations due to reprogramming-associated cellular rejuvenation which resets the aging hallmarks of donor cells. Given the prominent role of aging for the development and manifestation of late-onset NDDs, this suggests that this approach is not the most suitable to accurately model age-related diseases. Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows the possibility to generate patient-derived neurons that maintain aging and epigenetic signatures of the donor. This aspect may be advantageous for investigating the role of aging in neurodegeneration and for finely dissecting underlying pathological mechanisms. Here, we will compare iPSC and iN models as regards the aging status and explore how this difference is reported to affect the phenotype of NDD in vitro models.

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The potential role of cholesterol in Parkinson’s disease neuropathology: perpetrator or victim

Alrouji,

Al-Kuraishy,

Al-Mahammadawy

et al. 2023

Neurol Sci

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Age-related pathological impairments in directly reprogrammed dopaminergic neurons derived from patients with idiopathic Parkinson’s disease

Cited by 25 publications

References 42 publications

Identification of DOT1L inhibitor in a screen for factors that promote dopaminergic neuron survival

Identification of DOT1L inhibitor in a screen for factors that promote dopaminergic neuron survival

Induced pluripotent stem cell-derived and directly reprogrammed neurons to study neurodegenerative diseases: The impact of aging signatures

The potential role of cholesterol in Parkinson’s disease neuropathology: perpetrator or victim

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