LMK235, a small molecule inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson’s disease

Mutations in the GBA1 gene encoding the lysosomal enzyme β-glucocerebrosidase (GCase) represent the most common risk factor for Parkinson’s disease (PD). GCase has been identified as a potential therapeutic target for PD and current efforts are focused on chemical chaperones to translocate mutant GCase into lysosomes. However, for several GBA1-linked forms of PD and PD associated with mutations in LRRK2, DJ-1, and PARKIN, activating wild-type GCase represents an alternative approach. We developed a new small-molecule modulator of GCase called S-181 that increased wild-type GCase activity in iPSC-derived dopaminergic neurons from sporadic PD patients, as well as patients carrying the 84GG mutation in GBA1, or mutations in LRRK2, DJ-1, or PARKIN who had decreased GCase activity. S-181 treatment of these PD iPSC-derived dopaminergic neurons partially restored lysosomal function and lowered accumulation of oxidized dopamine, glucosylceramide and α-synuclein. Moreover, S-181 treatment of mice heterozygous for the D409V GBA1 mutation (Gba1D409V/+) resulted in activation of wild-type GCase and consequent reduction of GCase lipid substrates and α-synuclein in mouse brain tissue. Our findings point to activation of wild-type GCase by small-molecule modulators as a potential therapeutic approach for treating familial and sporadic forms of PD that exhibit decreased GCase activity.

Download Full-text

STEP61 is a substrate of the E3 ligase parkin and is upregulated in Parkinson’s disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1417423112 ◽

2015 ◽

Vol 112 (4) ◽

pp. 1202-1207 ◽

Cited By ~ 34

Author(s):

Pradeep K. Kurup ◽

Jian Xu ◽

Rita Alexandra Videira ◽

Chimezie Ononenyi ◽

Graça Baltazar ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protein Tyrosine Phosphatase ◽

Dopaminergic Neurons ◽

Tyrosine Phosphatase ◽

E3 Ligase ◽

Substantia Nigra Pars Compacta ◽

Rat Striatum ◽

Protein Tyrosine ◽

Cellular Models

Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The loss of SNc dopaminergic neurons affects the plasticity of striatal neurons and leads to significant motor and cognitive disabilities during the progression of the disease. PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in genetic and sporadic PD. Mutations in PARK2 are a major contributing factor in the early onset of autosomal-recessive juvenile parkinsonism (AR-JP), although the mechanisms by which a disruption in parkin function contributes to the pathophysiology of PD remain unclear. Here we demonstrate that parkin is an E3 ligase for STEP61 (striatal-enriched protein tyrosine phosphatase), a protein tyrosine phosphatase implicated in several neuropsychiatric disorders. In cellular models, parkin ubiquitinates STEP61 and thereby regulates its level through the proteasome system, whereas clinically relevant parkin mutants fail to do so. STEP61 protein levels are elevated on acute down-regulation of parkin or in PARK2 KO rat striatum. Relevant to PD, STEP61 accumulates in the striatum of human sporadic PD and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. The increase in STEP61 is associated with a decrease in the phosphorylation of its substrate ERK1/2 and the downstream target of ERK1/2, pCREB [phospho-CREB (cAMP response element-binding protein)]. These results indicate that STEP61 is a novel substrate of parkin, although further studies are necessary to determine whether elevated STEP61 levels directly contribute to the pathophysiology of PD.

Download Full-text

Small Molecule c-jun-N-Terminal Kinase Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease

ACS Chemical Neuroscience ◽

10.1021/cn100109k ◽

2011 ◽

Vol 2 (4) ◽

pp. 198-206 ◽

Cited By ~ 42

Author(s):

Jeremy W. Chambers ◽

Alok Pachori ◽

Shannon Howard ◽

Michelle Ganno ◽

Donald Hansen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Small Molecule ◽

Dopaminergic Neurons ◽

Kinase Inhibitors

Download Full-text

Mechanistic model-driven exometabolomic characterisation of human dopaminergic neuronal metabolism

10.1101/2021.06.30.450562 ◽

2021 ◽

Author(s):

German Preciat ◽

Edinson L. Moreno ◽

Agnieszka Wegrzyn ◽

Cornelius C.W. Willacey ◽

Jennifer Modamio ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Mechanistic Model ◽

Metabolic Dysfunction ◽

Spearman Rank ◽

Model Driven ◽

Cellular Models ◽

Neuronal Metabolism

Patient-derived cellular models are a powerful approach to study human disease, especially neurodegenerative diseases, such as Parkinson's disease, where affected primary neurons, e.g., substantia nigra dopaminergic neurons, are almost inaccessible. Starting with a comprehensive generic reconstruction of human metabolism, Recon3D, we generated a high-quality, constraint-based, genome-scale, in silico model of human dopaminergic neuronal metabolism (iDopaNeuro1). It is a synthesis of extensive manual curation of the biochemical literature on neuronal metabolism, together with novel, quantitative, transcriptomic and targeted exometabolomic data from human stem cell-derived, midbrain-specific, dopaminergic neurons in vitro. Thermodynamic constraint-based modelling with iDopaNeuro1 is qualitatively accurate (92% correct) and quantitatively accurate (Spearman rank 0.7) at predicting metabolite secretion or uptake, given quantitative exometabolomic constraints on uptakes, or secretions, respectively. iDopaNeuro1 is also qualitatively accurate at predicting the consequences of metabolic perturbations, e.g., complex I inhibition (Spearman rank 0.69) in a manner consistent with literature on monogenic mitochondrial Parkinson's disease. The iDopaNeuro1 model provides a foundation for a quantitative systems biochemistry approach to metabolic dysfunction in Parkinson's disease. Moreover, the plethora of novel mathematical and computational approaches required to develop it are generalisable to study any other disease associated with metabolic dysfunction.

Download Full-text

Long-term exposure to GDNF induces dephosphorylation of Ret, AKT, and ERK1/2, and is ineffective at protecting midbrain dopaminergic neurons in cellular models of Parkinson's disease

Molecular and Cellular Neuroscience ◽

10.1016/j.mcn.2021.103684 ◽

2021 ◽

pp. 103684

Author(s):

V. Mesa-Infante ◽

D. Afonso-Oramas ◽

J. Salas-Hernández ◽

J. Rodríguez-Núñez ◽

P. Barroso-Chinea

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Cellular Models ◽

Midbrain Dopaminergic Neurons

Download Full-text

Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804198115 ◽

2018 ◽

Vol 115 (41) ◽

pp. 10481-10486 ◽

Cited By ~ 56

Author(s):

Jordi Pujols ◽

Samuel Peña-Díaz ◽

Diana F. Lázaro ◽

Francesca Peccati ◽

Francisca Pinheiro ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Small Molecule ◽

Dopaminergic Neurons ◽

High Throughput Screening ◽

Protein Misfolding ◽

Lewy Bodies ◽

Molar Ratio ◽

Lewy Neurites

Parkinson’s disease (PD) is characterized by a progressive loss of dopaminergic neurons, a process that current therapeutic approaches cannot prevent. In PD, the typical pathological hallmark is the accumulation of intracellular protein inclusions, known as Lewy bodies and Lewy neurites, which are mainly composed of α-synuclein. Here, we exploited a high-throughput screening methodology to identify a small molecule (SynuClean-D) able to inhibit α-synuclein aggregation. SynuClean-D significantly reduces the in vitro aggregation of wild-type α-synuclein and the familiar A30P and H50Q variants in a substoichiometric molar ratio. This compound prevents fibril propagation in protein-misfolding cyclic amplification assays and decreases the number of α-synuclein inclusions in human neuroglioma cells. Computational analysis suggests that SynuClean-D can bind to cavities in mature α-synuclein fibrils and, indeed, it displays a strong fibril disaggregation activity. The treatment with SynuClean-D of two PD Caenorhabditis elegans models, expressing α-synuclein either in muscle or in dopaminergic neurons, significantly reduces the toxicity exerted by α-synuclein. SynuClean-D–treated worms show decreased α-synuclein aggregation in muscle and a concomitant motility recovery. More importantly, this compound is able to rescue dopaminergic neurons from α-synuclein–induced degeneration. Overall, SynuClean-D appears to be a promising molecule for therapeutic intervention in Parkinson’s disease.

Download Full-text

Automated microuidic cell culture of stem cell derived dopaminergic neurons in Parkinson’s disease

10.1101/209957 ◽

2017 ◽

Author(s):

Khalid I.W. Kane ◽

Edinson Lucumi Moreno ◽

Siham Hachi ◽

Moriz Walter ◽

Javier Jarazo ◽

...

Keyword(s):

Parkinson’S Disease ◽

Cell Culture ◽

Parkinson's Disease ◽

Stem Cell ◽

Dopaminergic Neurons ◽

Disease Patient ◽

Motor Dysfunction ◽

Patient Specific ◽

Cellular Models

AbstractParkinson’s disease is a slowly progressive neurodegenerative disease characterised by dysfunction and death of selectively vulnerable midbrain dopaminergic neurons leading mainly to motor dysfunction, but also other non-motor symptoms. The development of human in vitro cellular models with similar phenotypic characteristics to selectively vulnerable neurons is a major challenge in Parkinson’s disease research. We constructed a fully automated cell culture platform optimised for long-term maintenance and monitoring of induced pluripotent stem cell derived neurons in three dimensional microfluidic cell culture devices. The system can be flexibly adapted to various experimental protocols and features time-lapse imaging microscopy for quality control and electrophysiology monitoring to assess neuronal activity. Using this system, we continuously monitored the differentiation of Parkinson’s disease patient derived human neuroepithelial stem cells into midbrain specific dopaminergic neurons. Calcium imaging confirmed the electrophysiological activity of differentiated neurons and immunostaining confirmed the efficiency of the differentiation protocol. This system is the first example of a fully automated Organ-on-a-Chip culture and enables a versatile array of in vitro experiments for patient-specific disease modelling.

Download Full-text