The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting ...circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments.
For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial.
A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD.
The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.
Neuroinflammation and mitochondrial dysfunction, key mechanisms in the pathogenesis of Parkinson's disease (PD), are usually explored independently. Loss‐of‐function mutations of PARK2 and PARK6, ...encoding the E3 ubiquitin protein ligase Parkin and the mitochondrial serine/threonine kinase PINK1, account for a large proportion of cases of autosomal recessive early‐onset PD. PINK1 and Parkin regulate mitochondrial quality control and have been linked to the modulation of innate immunity pathways. We report here an exacerbation of NLRP3 inflammasome activation by specific inducers in microglia and bone marrow‐derived macrophages from Park2−/− and Pink1−/− mice. The caspase 1‐dependent release of IL‐1β and IL‐18 was, therefore, enhanced in Park2−/− and Pink1−/− cells. This defect was confirmed in blood‐derived macrophages from patients with PARK2 mutations and was reversed by MCC950, which specifically inhibits NLRP3 inflammasome complex formation. Enhanced NLRP3 signaling in Parkin‐deficient cells was accompanied by a lack of induction of A20, a well‐known negative regulator of the NF‐κB pathway recently shown to attenuate NLRP3 inflammasome activity. We also found an inverse correlation between A20 abundance and IL‐1β release, in human macrophages challenged with NLRP3 inflammasome inducers. Overall, our observations suggest that the A20/NLRP3‐inflammasome axis participates in the pathogenesis of PARK2‐linked PD, paving the way for the exploration of its potential as a biomarker and treatment target.
Main Points
Parkin deficiency exacerbates the NLRP3 inflammasome by disrupting A20‐dependent negative regulation.
NLRP3 inflammasome overactivation and A20 deregulation were also observed in blood‐derived macrophages from patients with PARK2 mutations.
Objective
This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain ...stimulation (STN‐DBS) in Parkinson disease.
Methods
Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS‐), and noncarriers with or without DBS (GBA‐DBS+, GBA‐DBS‐). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status.
Results
Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS‐, 98 GBA‐DBS+, and 128 GBA‐DBS‐ subjects), who were longitudinally followed (range = 36–60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA‐DBS‐ subjects (95% confidence interval CI = −2.35 to −1.69), 1.71 points/yr more than GBA+DBS‐ subjects (95% CI = −2.14 to −1.28), and 1.49 points/yr more than GBA‐DBS+ subjects (95% CI = −1.80 to −1.18).
Interpretation
Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN‐DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision‐making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN‐DBS so that alternative options may be considered. ANN NEUROL 2022;91:424–435
Mutations in the PTEN‐induced kinase 1 (PINK1) are causative of autosomal recessive Parkinson's disease (PD). We have previously reported that PINK1 is activated by mitochondrial depolarisation and ...phosphorylates serine 65 (Ser65) of the ubiquitin ligase Parkin and ubiquitin to stimulate Parkin E3 ligase activity. Here, we have employed quantitative phosphoproteomics to search for novel PINK1‐dependent phosphorylation targets in HEK (human embryonic kidney) 293 cells stimulated by mitochondrial depolarisation. This led to the identification of 14,213 phosphosites from 4,499 gene products. Whilst most phosphosites were unaffected, we strikingly observed three members of a sub‐family of Rab GTPases namely Rab8A, 8B and 13 that are all phosphorylated at the highly conserved residue of serine 111 (Ser111) in response to PINK1 activation. Using phospho‐specific antibodies raised against Ser111 of each of the Rabs, we demonstrate that Rab Ser111 phosphorylation occurs specifically in response to PINK1 activation and is abolished in HeLa PINK1 knockout cells and mutant PINK1 PD patient‐derived fibroblasts stimulated by mitochondrial depolarisation. We provide evidence that Rab8A GTPase Ser111 phosphorylation is not directly regulated by PINK1 in vitro and demonstrate in cells the time course of Ser111 phosphorylation of Rab8A, 8B and 13 is markedly delayed compared to phosphorylation of Parkin at Ser65. We further show mechanistically that phosphorylation at Ser111 significantly impairs Rab8A activation by its cognate guanine nucleotide exchange factor (GEF), Rabin8 (by using the Ser111Glu phosphorylation mimic). These findings provide the first evidence that PINK1 is able to regulate the phosphorylation of Rab GTPases and indicate that monitoring phosphorylation of Rab8A/8B/13 at Ser111 may represent novel biomarkers of PINK1 activity in vivo. Our findings also suggest that disruption of Rab GTPase‐mediated signalling may represent a major mechanism in the neurodegenerative cascade of Parkinson's disease.
Synopsis
The Parkinson's disease‐mutated PINK1 kinase phosphorylates Parkin and ubiquitin. Phosphoproteomic screening reveals Rab8A, Rab8B and Rab13 GTPases as some of only few additional targets whose phosphorylation depends on PINK1 during mitophagy.
Activated PINK1 indirectly controls phosphorylation of serine 111 of Rab8A and closely related Rab GTPases.
Biochemical and cellular analysis imply an unknown intermediate PINK1‐dependent Rab8A Ser111 kinase or phosphatase.
PINK1‐directed activation of Parkin E3 ligase activity is independent of Rab8A Ser111 phosphorylation
Phosphorylation at Ser111 inhibits Rab8A activation by its guanine exchange factor, Rabin8.
Ser111 modification of Rab8A, Rab8B and Rab13 represent some of only few PINK1‐dependent phosphorylation events and may regulate GTPase function during mitophagy.
Background and Purpose
This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these ...treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway.
Methods
Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging–guided focused ultrasound surgery MRgFUS of the following targets: subthalamic nucleus STN, ventrolateral thalamus, and pallidum internum GPi). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump LCIG) was also included. Changes in motor features, health‐related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high‐class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered.
Results
Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN‐DBS is the best‐studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi‐DBS can also be offered. For early PD with early fluctuations, STN‐DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment‐resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication‐resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended.
Conclusions
Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups.
Recommendations for invasive therapies for the treatment of specific subgroups of patients with Parkinson's disease for which data are available. Formal GRADE‐Recommendations are indicated in colours. Clinical practice statements are provided in grey.
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