Iron deficiency in parkinsonism : region-specific iron dysregulation in Parkinson's disease and multiple system atrophy

Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron

Deposits of disease-associated alpha-synuclein may be present in the dura mater in Lewy body disorders: implications for potential inadvertent transmission by surgery

Deposition of alpha-synuclein in the brain is a hallmark of Lewy body disorders. Alpha-synuclein has been considered to show prion-like properties. Prion diseases can be transmitted by the transplantation of cadaveric dura mater causing iatrogenic Creutzfeldt-Jakob disease. Recent observations of amyloid-β deposition in dural grafts support the seeding properties of amyloid-β. Here we assessed the presence of alpha-synuclein in dura mater samples as a potential transmissible seed source. We immunostained 32 postmortem dura mater samples; 16 cases with Lewy-body disorder (LBD) showing different pathology stages and 16 non-LBD cases for phosphorylated (Ser129) and disease-associated (5G4) alpha-synuclein. Disease-associated alpha-synuclein aggregates were identified in intradural nerve fibres and associated with a vessel in a single LBD-Braak stage 4 case. We conclude that alpha-synuclein is detectable, although rarely, in dura mater samples in patients with LBD. The risk of potential transmissibility of dural alpha-synuclein deserves assessment by complementary experimental studies

Tumor necrosis factor‐α underlies loss of cortical dendritic spine density in a mouse model of congestive heart failure

BACKGROUND: Heart failure (HF) is a progressive disorder characterized by reduced cardiac output and increased peripheral resistance, ultimately leading to tissue perfusion deficits and devastating consequences for several organs including the brain. We previously described a tumor necrosis factor-α (TNF-α)-dependent enhancement of posterior cerebral artery tone and concomitant reduced cerebral blood flow in a mouse model of early HF in which blood pressure remains minimally affected. HF is often associated with cognitive impairments such as memory deficits, even before any overt changes in brain structure and function occur. The pathophysiology underlying the development of cognitive impairments in HF is unknown, and appropriate treatment strategies are lacking.METHODS AND RESULTS: We used a well-established mouse model in which HF was induced by experimental myocardial infarction produced by permanent surgical ligation of the left anterior descending coronary artery (infarct size ≈25% of the left ventricular wall). Ligated mice developed enlarged hearts, congested lungs, and reduced cardiac output and blood pressure, with elevated peripheral resistance within 6 to 8 weeks after ligation. In this study, we demonstrated the significance of the proinflammatory cytokine TNF-α during HF-mediated neuroinflammation and associated impaired hippocampus-independent nonspatial episodic memory function. Augmented cerebral TNF-α expression and microglial activation in HF mice, indicative of brain inflammation, were accompanied by morphological changes and significant reduction of cortical dendritic spines (61.39±8.61% for basal and 61.04±9.18% for apical spines [P<0.001]). The significance of TNF-α signaling during the observed HF-mediated neurodegenerative processes is supported by evidence showing that sequestration or genetic deletion of TNF-α ameliorates the observed reduction of cortical dendritic spines (33.51±7.63% for basal and 30.13±6.98% for apical spines in wild-type mice treated with etanercept; 17.09±6.81% for basal and 17.21±7.29% for apical spines in TNF-α(-/-)). Moreover, our data suggest that alterations in cerebral serum and glucocorticoid-inducible kinase 1 (SgK1) expression and phosphorylation during HF may be TNF-α dependent and that an increase of SgK1 phosphorylation potentially plays a role in the HF-associated reduction of dendritic spine density.CONCLUSIONS: Our findings demonstrate that TNF-α plays a pivotal role in HF-mediated neuroinflammation and associated alterations of cortical dendritic spine density and has the potential to reveal novel treatment strategies for HF-associated memory deficits

Increased markers of cardiac vagal activity in leucine-rich repeat kinase 2-associated Parkinson's disease.

PurposeCardiac autonomic dysfunction manifests as reduced heart rate variability (HRV) in idiopathic Parkinson's disease (PD), but no significant reduction has been found in PD patients who carry the LRRK2 mutation. Novel HRV features have not been investigated in these individuals. We aimed to assess cardiac autonomic modulation through standard and novel approaches to HRV analysis in individuals who carry the LRRK2 G2019S mutation.MethodsShort-term electrocardiograms were recorded in 14 LRRK2-associated PD patients, 25 LRRK2-non-manifesting carriers, 32 related non-carriers, 20 idiopathic PD patients, and 27 healthy controls. HRV measures were compared using regression modeling, controlling for age, sex, mean heart rate, and disease duration. Discriminant analysis highlighted the feature combination that best distinguished LRRK2-associated PD from controls.ResultsBeat-to-beat and global HRV measures were significantly increased in LRRK2-associated PD patients compared with controls (e.g., deceleration capacity of heart rate: p = 0.006) and idiopathic PD patients (e.g., 8th standardized moment of the interbeat interval distribution: p = 0.0003), respectively. LRRK2-associated PD patients also showed significantly increased irregularity of heart rate dynamics, as quantified by Rényi entropy, when compared with controls (p = 0.002) and idiopathic PD patients (p = 0.0004). Ordinal pattern statistics permitted the identification of LRRK2-associated PD individuals with 93% sensitivity and 93% specificity. Consistent results were found in a subgroup of LRRK2-non-manifesting carriers when compared with controls.ConclusionsIncreased beat-to-beat HRV in LRRK2 G2019S mutation carriers compared with controls and idiopathic PD patients may indicate augmented cardiac autonomic cholinergic activity, suggesting early impairment of central vagal feedback loops in LRRK2-associated PD

Investigating Voice as a Biomarker for Leucine-Rich Repeat Kinase 2-Associated Parkinson's Disease

We investigate the potential association between leucine-rich repeat kinase 2 (LRRK2) mutations and voice. Sustained phonations ('aaah' sounds) were recorded from 7 individuals with LRRK2-associated Parkinson's disease (PD), 17 participants with idiopathic PD (iPD), 20 non-manifesting LRRK2-mutation carriers, 25 related non-carriers, and 26 controls. In distinguishing LRRK2-associated PD and iPD, the mean sensitivity was 95.4% (SD 17.8%) and mean specificity was 89.6% (SD 26.5%). Voice features for non-manifesting carriers, related non-carriers, and controls were much less discriminatory. Vocal deficits in LRRK2-associated PD may be different than those in iPD. These preliminary results warrant longitudinal analyses and replication in larger cohorts

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease.

OBJECTIVE: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. METHODS: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. RESULTS: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. INTERPRETATION: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82-94

Beyond the synucleinopathies: alpha synuclein as a driving force in neurodegenerative comorbidities

Abstract The fundamental role that alpha-synuclein (aSyn) plays in the pathogenesis of neurodegenerative synucleinopathies, including Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, is a well-accepted fact. A wealth of experimental evidence has linked this relatively small but ubiquitously expressed protein to a plethora of cytopathologic mechanisms and suggests that aSyn may be capable of seeding the progressive spread of synucleinopathy throughout the brain. Beyond the synucleinopathies, the abnormal deposition of aSyn is frequently seen in a variety of other neurodegenerative proteinopathies including Alzheimer’s disease. In spite of the fact that the frequency of concomitant aSyn pathology in these disorders is such that it can be considered the rule rather than the exception, the potential role that aSyn may have in these disorders has received relatively little attention. In this article we postulate that aSyn may in fact be a key protein in driving the pathogenic processes in neurodegenerative comorbidities. In addition to reviewing the frequency of concomitant deposition of aSyn in the neurodegenerative proteinopathies, we also consider our current understanding of the interaction of aSyn with other neurodegenerative disease-associated proteins, including tau, TDP-43, amyloid-β and prion protein, in the context of neuropathologic studies describing the anatomical sites of potential concomitant pathology. We conclude that a growing body of evidence, encompassing neuropathology studies in human brain, animal models of concomitant proteinopathies and studies employing sophisticated methods of probing protein-protein interaction, cumulatively suggest that aSyn is well positioned to exert a strong influence on the pathogenesis of the neurodegenerative comorbidities. We hope to stimulate research in this emerging field and consider that future studies exploring the contribution of aSyn to the pathogenic processes in neurodegenerative comorbidities may provide critical information pertaining to diagnosis and the development of vital disease modifying treatments for these devastating diseases

The prion hypothesis in Parkinson's disease: Braak to the future

Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder typified by the presence of intraneuronal inclusions containing aggregated alpha synuclein (αsyn). The progression of parkinsonian pathology and clinical phenotype has been broadly demonstrated to follow a specific pattern, most notably described by Braak and colleagues. In more recent times it has been hypothesized that αsyn itself may be a critical factor in mediating transmission of disease pathology from one brain area to another. Here we investigate the growing body of evidence demonstrating the ability of αsyn to spread transcellularly and induce pathological aggregation affecting neurons by permissive templating and provide a critical analysis of some irregularities in the hypothesis that the progression of PD pathology may be mediated by such a prion-like process. Finally we discuss some key questions that remain unanswered which are vital to determining the potential contribution of a prion-like process to the pathogenesis of PD

An AI-guided screen identifies probucol as an enhancer of mitophagy through modulation of lipid droplets.

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage

Tumor Necrosis Factor‐α Underlies Loss of Cortical Dendritic Spine Density in a Mouse Model of Congestive Heart Failure

BACKGROUND: Heart failure (HF) is a progressive disorder characterized by reduced cardiac output and increased peripheral resistance, ultimately leading to tissue perfusion deficits and devastating consequences for several organs including the brain. We previously described a tumor necrosis factor-α (TNF-α)-dependent enhancement of posterior cerebral artery tone and concomitant reduced cerebral blood flow in a mouse model of early HF in which blood pressure remains minimally affected. HF is often associated with cognitive impairments such as memory deficits, even before any overt changes in brain structure and function occur. The pathophysiology underlying the development of cognitive impairments in HF is unknown, and appropriate treatment strategies are lacking.METHODS AND RESULTS: We used a well-established mouse model in which HF was induced by experimental myocardial infarction produced by permanent surgical ligation of the left anterior descending coronary artery (infarct size ≈25% of the left ventricular wall). Ligated mice developed enlarged hearts, congested lungs, and reduced cardiac output and blood pressure, with elevated peripheral resistance within 6 to 8 weeks after ligation. In this study, we demonstrated the significance of the proinflammatory cytokine TNF-α during HF-mediated neuroinflammation and associated impaired hippocampus-independent nonspatial episodic memory function. Augmented cerebral TNF-α expression and microglial activation in HF mice, indicative of brain inflammation, were accompanied by morphological changes and significant reduction of cortical dendritic spines (61.39±8.61% for basal and 61.04±9.18% for apical spines [P<0.001]). The significance of TNF-α signaling during the observed HF-mediated neurodegenerative processes is supported by evidence showing that sequestration or genetic deletion of TNF-α ameliorates the observed reduction of cortical dendritic spines (33.51±7.63% for basal and 30.13±6.98% for apical spines in wild-type mice treated with etanercept; 17.09±6.81% for basal and 17.21±7.29% for apical spines in TNF-α(-/-)). Moreover, our data suggest that alterations in cerebral serum and glucocorticoid-inducible kinase 1 (SgK1) expression and phosphorylation during HF may be TNF-α dependent and that an increase of SgK1 phosphorylation potentially plays a role in the HF-associated reduction of dendritic spine density.CONCLUSIONS: Our findings demonstrate that TNF-α plays a pivotal role in HF-mediated neuroinflammation and associated alterations of cortical dendritic spine density and has the potential to reveal novel treatment strategies for HF-associated memory deficits