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Neurotherapeutics : the Journal of the... Jul 2023Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be...
Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.
Topics: Animals; Mice; Apoptosis; Dopaminergic Neurons; Lipids; Mice, Inbred C57BL; Parkinson Disease; Parkinsonian Disorders; Phenotype; Reactive Oxygen Species; Humans
PubMed: 37133631
DOI: 10.1007/s13311-023-01382-4 -
Journal of Neurology Dec 2021In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing... (Review)
Review
In March 2020, WHO declared Covid-19 outbreak pandemic. There has been increasing evidence that frail, old, multi-pathological patients are at greater risk of developing severe Covid-19 infection than younger, healthy ones. Covid-19's impact on Parkinson's Disease (PD) patients could be analysed through both the influence on PD patients' health and their risk of developing severe Covid-19, and the consequences of lockdown and restrictive measures on mental and cognitive health on both patients and caregivers. Moreover, there are critical issues to be considered about patients' care and management through an unprecedented time like this. One important issue to consider is physiotherapy, as most patients cannot keep exercising because of restrictive measures which has profoundly impacted on their health. Lastly, the relationship between PD and Sars-Cov2 may be even more complicated than it seems as some studies have hypothesized a possible Covid-19-induced parkinsonism. Hereby, we review the state of the art about the relationship between Covid-19 and Parkinson's Disease, focusing on each of these five points.
Topics: COVID-19; Communicable Disease Control; Humans; Parkinson Disease; RNA, Viral; SARS-CoV-2
PubMed: 34313818
DOI: 10.1007/s00415-021-10721-4 -
Biomolecules Jul 2023Manganese (Mn) exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure. In this latter scenario, the target areas extend... (Review)
Review
Manganese (Mn) exposure has evolved from acute, high-level exposure causing manganism to low, chronic lifetime exposure. In this latter scenario, the target areas extend beyond the globus pallidus (as seen with manganism) to the entire basal ganglia, including the substantia nigra pars compacta. This change of exposure paradigm has prompted numerous epidemiological investigations of the occurrence of Parkinson's disease (PD), or parkinsonism, due to the long-term impact of Mn. In parallel, experimental research has focused on the underlying pathogenic mechanisms of Mn and its interactions with genetic susceptibility. In this review, we provide evidence from both types of studies, with the aim to link the epidemiological data with the potential mechanistic interpretation.
Topics: Humans; Manganese; Parkinsonian Disorders; Parkinson Disease; Genetic Predisposition to Disease
PubMed: 37627255
DOI: 10.3390/biom13081190 -
Journal of Parkinson's Disease 2021Parkinson's disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential... (Review)
Review
Parkinson's disease (PD) is thought to be caused by a combination of genetic and environmental factors. Bacterial or viral infection has been proposed as a potential risk factor, and there is supporting although not entirely consistent epidemiologic and basic science evidence to support its role. Encephalitis caused by influenza has included parkinsonian features. Epidemiological evidence is most compelling for an association between PD and hepatitis C virus. Infection with Helicobacter pylori may be associated not only with PD risk but also response to levodopa. Rapidly evolving knowledge regarding the role of the microbiome also suggests a role of resident bacteria in PD risk. Biological plausibility for the role for infectious agents is supported by the known neurotropic effects of specific viruses, particular vulnerability of the substantia nigra and even the promotion of aggregation of alpha-synuclein. A common feature of implicated viruses appears to be production of high levels of cytokines and chemokines that can cross the blood-brain barrier leading to microglial activation and inflammation and ultimately neuronal cell death. Based on multiple avenues of evidence it appears likely that specific bacterial and particularly viral infections may increase vulnerability to PD. The implications of this for PD prevention requires attention and may be most relevant once preventive treatments for at-risk populations are developed.
Topics: Bacterial Infections; Gastrointestinal Microbiome; Humans; Parkinson Disease; Virus Diseases
PubMed: 33361610
DOI: 10.3233/JPD-202279 -
Current Neurology and Neuroscience... Apr 2021There has been an exponential growth in functional connectomics research in neurodegenerative disorders. This review summarizes the recent findings and limitations of... (Review)
Review
PURPOSE OF REVIEW
There has been an exponential growth in functional connectomics research in neurodegenerative disorders. This review summarizes the recent findings and limitations of the field in Parkinson's disease (PD) and atypical parkinsonian syndromes.
RECENT FINDINGS
Increasingly more sophisticated methods ranging from seed-based to network and whole-brain dynamic functional connectivity have been used. Results regarding the disruption in the functional connectome vary considerably based on disease severity and phenotypes, and treatment status in PD. Non-motor symptoms of PD also link to the dysfunction in heterogeneous networks. Studies in atypical parkinsonian syndromes are relatively scarce. An important clinical goal of functional connectomics in neurodegenerative disorders is to establish the presence of pathology, track disease progression, predict outcomes, and monitor treatment response. The obstacles of reliability and reproducibility in the field need to be addressed to improve the potential of the functional connectome as a biomarker for these purposes in PD and atypical parkinsonian syndromes.
Topics: Connectome; Humans; Multiple System Atrophy; Parkinson Disease; Parkinsonian Disorders; Reproducibility of Results; Supranuclear Palsy, Progressive
PubMed: 33817766
DOI: 10.1007/s11910-021-01111-4 -
Nature Communications Nov 2023The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in...
The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.
Topics: Animals; Humans; Mice; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra; Dopaminergic Neurons; Macaca; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37980356
DOI: 10.1038/s41467-023-43213-2 -
Journal of Parkinson's Disease 2022Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In... (Review)
Review
Levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD), occurs in ∼30% of patients after five years' treatment with levodopa. In atypical parkinsonism, LID occurs less frequently than in PD. Lower frequency of LID in atypical parkinsonism has traditionally been attributed to lower amounts of levodopa used by these patients; however, recent studies have shown lower frequency of LID in atypical parkinsonism compared with PD when adjusting for levodopa dose. The mechanism of LID is complex but requires pulsatile levodopa stimulation, progressive presynaptic dopaminergic degeneration, and a relatively intact postsynaptic dopaminergic system. The globus pallidus internus (GPi), the main inhibitory nucleus of the basal ganglia, may play a major role in the development and treatment of LID. Surgical lesioning of the posteroventral GPi is directly antidyskinetic; animal models showing GPi-associated striatal neurons are directly responsible for the development of LID. However, other cortical areas, particularly the primary sensory and motor cortices may also play a role in LID. In some cases of atypical parkinsonism, particularly progressive supranuclear palsy and corticobasal degeneration, severe degeneration of the GPi, a so-called "autopallidotomy," may explain the absence of LID in these patients. In other atypical parkinsonisms, such as PD dementia and dementia with Lewy bodies, the lower incidence of LID may partly be attributed to more striatal degeneration but likely also relates to the degeneration of the motor cortex and resultant network dysfunction. Overall, atypical parkinsonism serves as a natural model that may ultimately reveal more effective therapies for LID.
Topics: Animals; Antiparkinson Agents; Basal Ganglia; Dyskinesias; Globus Pallidus; Levodopa; Parkinson Disease; Parkinsonian Disorders
PubMed: 36120793
DOI: 10.3233/JPD-223491 -
JAMA Network Open Aug 2023Parkinsonism and Parkinson disease (PD) are known to result from repetitive head impacts from boxing. Repetitive head impacts from American football may also be...
IMPORTANCE
Parkinsonism and Parkinson disease (PD) are known to result from repetitive head impacts from boxing. Repetitive head impacts from American football may also be associated with increased risk of neurodegenerative pathologies that cause parkinsonism, yet in vivo research on the association between football play and PD is scarce and limited by small samples and equivocal findings.
OBJECTIVE
To evaluate the association between football participation and self-reported parkinsonism or PD diagnosis.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study leveraged data from the online Fox Insight study. Participants completed online questionnaires and self-reported whether they currently had a diagnosis of Parkinson disease or parkinsonism by a physician or other health care professional. In November 2020, the Boston University Head Impact Exposure Assessment was launched for data collection on repetitive head impacts. Data used for this manuscript were obtained from the Fox Insight database on June 9, 2022. A total of 1875 men who endorsed playing any organized sport were included. Former athletes were divided into those who participated in football (n = 729 [38.9%]) and those who participated in other sports (reference group).
EXPOSURES
Self-reported participation in football, duration and level of football play, age at first exposure.
MAIN OUTCOMES AND MEASURES
Logistic regression tested associations between PD status and history of football play, duration of football play, highest level played, and age at first exposure, controlling for age, education, history of diabetes or heart disease, body mass index, history of traumatic brain injury with loss of consciousness, and family history of PD.
RESULTS
In this sample of 1875 men (mean [SD] age, 67.69 [9.84] years) enriched for parkinsonism or PD (n = 1602 [85.4%]), 729 (38.9%) played football (mean [SD] duration, 4.35 [2.91] years). History of playing football was associated with higher odds of having a parkinsonism or PD diagnosis (odds ratio [OR], 1.61; 95% CI, 1.19-2.17). Among the entire sample, longer duration of play was associated with higher odds of having a parkinsonism or PD diagnosis (OR, 1.12; 95% CI, 1.06-1.19). Among football players, longer duration of football play (OR, 1.12; 95% CI, 1.02-1.23) and higher level of play (OR, 2.93; 95% CI, 1.28-6.73) were associated with higher odds of having parkinsonism or PD.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study of participants enriched for PD, participation in football was associated with higher odds of having a reported parkinsonism or PD diagnosis.
Topics: Male; Humans; Aged; Football; Parkinson Disease; Cross-Sectional Studies; Universities
PubMed: 37566412
DOI: 10.1001/jamanetworkopen.2023.28644 -
Molecular Neurodegeneration Aug 2019Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson... (Review)
Review
Mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase, are among the most common known genetic risk factors for the development of Parkinson disease and related synucleinopathies. A great deal is known about GBA1, as mutations in GBA1 are causal for the rare autosomal storage disorder Gaucher disease. Over the past decades, significant progress has been made in understanding the genetics and cell biology of glucocerebrosidase. A least 495 different mutations, found throughout the 11 exons of the gene are reported, including both common and rare variants. Mutations in GBA1 may lead to degradation of the protein, disruptions in lysosomal targeting and diminished performance of the enzyme in the lysosome.Gaucher disease is phenotypically diverse and has both neuronopathic and non-neuronopathic forms. Both patients with Gaucher disease and heterozygous carriers are at increased risk of developing Parkinson disease and Dementia with Lewy Bodies, although our understanding of the mechanism for this association remains incomplete. There appears to be an inverse relationship between glucocerebrosidase and α-synuclein levels, and even patients with sporadic Parkinson disease have decreased glucocerebrosidase. Glucocerebrosidase may interact with α-synuclein to maintain basic cellular functions, or impaired glucocerebrosidase could contribute to Parkinson pathogenesis by disrupting lysosomal homeostasis, enhancing endoplasmic reticulum stress or contributing to mitochondrial impairment. However, the majority of patients with GBA1 mutations never develop parkinsonism, so clearly other risk factors play a role. Treatments for Gaucher disease have been developed that increase visceral glucocerebrosidase levels and decrease lipid storage, although they have yet to properly address the neurological defects associated with impaired glucocerebrosidase. Mouse and induced pluripotent stem cell derived models have improved our understanding of glucocerebrosidase function and the consequences of its deficiency. These models have been used to test novel therapies including chaperone proteins, histone deacetylase inhibitors, and gene therapy approaches that enhance glucocerebrosidase levels and could prove efficacious in the treatment of forms of parkinsonism. Consequently, this rare monogenic disorder, Gaucher disease, provides unique insights directly applicable to our understanding and treatment of Parkinson disease, a common and complex neurodegenerative disorder.
Topics: Animals; Glucosylceramidase; Humans; Induced Pluripotent Stem Cells; Lysosomes; Mitochondria; Parkinson Disease; Parkinsonian Disorders
PubMed: 31464647
DOI: 10.1186/s13024-019-0336-2 -
Neurological Sciences : Official... Mar 2024The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive...
The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.
Topics: Female; Humans; Middle Aged; Amyotrophic Lateral Sclerosis; Frontotemporal Dementia; tau Proteins; Parkinson Disease; Mutation; Parkinsonian Disorders
PubMed: 37730935
DOI: 10.1007/s10072-023-07081-4