Interactions of dopamine, iron, and alpha-synuclein linked to dopaminergic neuron vulnerability in Parkinson's disease and Neurodegeneration with Brain Iron Accumulation disorders.

Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors.

Mitochondrial Phenotypes in Parkinson's Diseases-A Focus on Human iPSC-Derived Dopaminergic Neurons.

Established disease models have helped unravel the mechanistic underpinnings of pathological phenotypes in Parkinson's disease (PD), the second most common neurodegenerative disorder. However, these discoveries have been limited to relatively simple cellular systems and animal models, which typically manifest with incomplete or imperfect recapitulation of disease phenotypes. The advent of induced pluripotent stem cells (iPSCs) has provided a powerful scientific tool for investigating the underlying molecular mechanisms of both familial and sporadic PD within disease-relevant cell types and patient-specific genetic backgrounds.

Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons.

During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative medicine and disease modeling. However, molecular fine tuning cell types to match their in vivo counterparts remains a challenge.

Direct targeting of wild-type glucocerebrosidase by antipsychotic quetiapine improves pathogenic phenotypes in Parkinson's disease models.

Current treatments for Parkinson's disease (PD) provide only symptomatic relief, with no disease-modifying therapies identified to date. Repurposing FDA-approved drugs to treat PD could significantly shorten the time needed for and reduce the costs of drug development compared with conventional approaches. We developed an efficient strategy to screen for modulators of β-glucocerebrosidase (GCase), a lysosomal enzyme that exhibits decreased activity in patients with PD, leading to accumulation of the substrate glucosylceramide and oxidized dopamine and α-synuclein, which contribute to PD pathogenesis.

Modeling Brain Pathology of Niemann-Pick Disease Type C Using Patient-Derived Neurons.

Background: Niemann-Pick disease type C (NPC) is a rare autosomal-recessive lysosomal storage disease that is also associated with progressive neurodegeneration. NPC shares many pathological features with Alzheimer's disease, including neurofibrillary tangles, axonal spheroids, β-amyloid deposition, and dystrophic neurites. Here, we examined if these pathological features could be detected in induced pluripotent stem cell (iPSC)-derived neurons from NPC patients.

The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by progressive bradykinesia, rigidity, resting tremor, and gait impairment, as well as a spectrum of non-motor symptoms including autonomic and cognitive dysfunction. The cardinal motor symptoms of PD stem from the loss of (SN) dopaminergic (DAergic) neurons, and it remains unclear why SN DAergic neurons are preferentially lost in PD. However, recent identification of several genetic PD forms suggests that mitochondrial and lysosomal dysfunctions play important roles in the degeneration of midbrain dopamine (DA) neurons.

Gelator length precisely tunes supramolecular hydrogel stiffness and neuronal phenotype in 3D culture.

The brain is one of the softest tissues in the body with storage moduli (G') that range from hundreds to thousands of pascals (Pa) depending upon the anatomic region. Furthermore, pathological processes such as injury, aging and disease can cause subtle changes in the mechanical properties throughout the central nervous system. However, these changes in mechanical properties lie within an extremely narrow range of moduli and there is great interest in understanding their effect on neuron biology.

A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease.

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of -linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons.

Author Correction: Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Variants in Miro1 Cause Alterations of ER-Mitochondria Contact Sites in Fibroblasts from Parkinson's Disease Patients.

Background: Although most cases of Parkinson´s disease (PD) are idiopathic with unknown cause, an increasing number of genes and genetic risk factors have been discovered that play a role in PD pathogenesis. Many of the PD-associated proteins are involved in mitochondrial quality control, e.g.

Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain.

Monoamine oxidase (MAO) metabolizes cytosolic dopamine (DA), thereby limiting auto-oxidation, but is also thought to generate cytosolic hydrogen peroxide (HO). We show that MAO metabolism of DA does not increase cytosolic HO but leads to mitochondrial electron transport chain (ETC) activity. This is dependent upon MAO anchoring to the outer mitochondrial membrane and shuttling electrons through the intermembrane space to support the bioenergetic demands of phasic DA release.

A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease.

Mutations in the 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 -linked forms of PD and PD associated with mutations in , , and , activating wild-type GCase represents an alternative approach.

The role of dopamine in the pathogenesis of GBA1-linked Parkinson's disease.

Our understanding of the molecular mechanisms underlying differential vulnerability of substantia nigra dopamine neurons in Parkinson's disease (PD) remains limited, and previous therapeutic efforts targeting rodent nigral neurons have not been successfully translated to humans. However, recent emergence of induced pluripotent stem cell technology has highlighted some fundamental differences between human and rodent midbrain dopamine neurons that may at least in part explain relative resistance of rodent neurons to degeneration in genetic models of PD. Using GBA1-linked PD as an example, we discuss cellular pathways that may predispose human neurons to degeneration in PD, including mitochondrial oxidant stress, elevated intracellular calcium, altered synaptic vesicle endocytosis, accumulation of oxidized dopamine and neuromelanin.

Conversion of Quinazoline Modulators from Inhibitors to Activators of β-Glucocerebrosidase.

Gaucher's disease is a lysosomal disease caused by mutations in the β-glucocerebrosidase gene ( GBA1 and GCase) that have been also linked to increased risk of Parkinson's disease (PD) and Diffuse Lewy body dementia. Prior studies have suggested that mutant GCase protein undergoes misfolding and degradation, and therefore, stabilization of the mutant protein represents an important therapeutic strategy in synucleinopathies. In this work, we present a structure-activity relationship (SAR) study of quinazoline compounds that serve as inhibitors of GCase.

Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells.

Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells.

Acid ceramidase inhibition ameliorates α-synuclein accumulation upon loss of GBA1 function.

GBA1 encodes the lysosomal enzyme β-glucocerebrosidase (GCase) which converts glucosylceramide into ceramide and glucose. Mutations in GBA1 lead to Gaucher's disease and are a major risk factor for Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), synucleinopathies characterized by accumulation of intracellular α-synuclein. In this study, we examined whether decreased ceramide that is observed in GCase-deficient cells contributes to α-synuclein accumulation.

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease.

Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson's disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation.