Conditional deletion of Ndufs4 in dopaminergic neurons promotes Parkinson’s disease-like non-motor symptoms without loss of dopamine neurons

Parkinson’s disease (PD) has been modeled in several animal species using the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized product 1-methyl-4-phenylpyridinium (MPP+). MPP+ selectively kills dopaminergic neurons in pars compacta of the substantia nigra, inducing parkinsonian symptoms in animals. Typically, neurotoxicity models of PD in zebrafish assess acute drug effects on locomotion. In the present study, we examined the lasting effects of MPP+ exposure and drug treatment in zebrafish larvae. Larvae were incubated in 500 μM MPP+, from 1 to 5 days post fertilization (dpf), followed by 24 h drug-free acclimation. At 6 dpf, the behavior was analyzed for locomotion, thigmotaxis, and sleep. Next, in separate assays we assessed the drug effects of brain injected glial cell-derived neurotrophic factor (GDNF) and 4-phenylbutyrate (PBA), co-incubated with MPP+. We show that MPP+ exposure consistently reduces swim distance, movement frequency, and cumulative time of movement; thus mimicking a parkinsonian phenotype of reduced movement. In contrast, MPP+ exposed larvae demonstrate reduced anxiety-like behavior and exhibit a sleep phenotype inconsistent with human PD: the larvae display longer sleep bouts, less sleep fragmentation, and more sleep. Previously reported rescuing effects of PBA were not replicated in this study. Moreover, whereas GDNF attenuated the sleep phenotype induced by MPP+, PBA augmented it. The current data suggest that MPP+ exposure generates a multifaceted phenotype in zebrafish and highlights that analyzing a narrow window of data can reveal effects that may be inconsistent with longer multi-parameter approaches. It further indicates that the model generally captures motor symptoms more faithfully than non-motor symptoms.

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Animal models of Parkinson's disease: a guide to selecting the optimal model for your research

Neuronal Signaling ◽

10.1042/ns20210026 ◽

2021 ◽

Author(s):

Joana Lama ◽

Yazead Buhidma ◽

Edward JR Fletcher ◽

Susan Duty

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Animal Models ◽

Dopaminergic Neurons ◽

Alpha Synuclein ◽

Motor Symptoms ◽

Multisystem Disorder ◽

Wide Range ◽

Non Motor Symptoms ◽

Selection Of

Parkinson’s disease (PD) is a complex, multisystem disorder characterised by alpha synuclein pathology, degeneration of nigrostriatal dopaminergic neurons, multifactorial pathogenetic mechanisms and expression of a plethora of motor and non-motor symptoms. Animal models of PD have already been instructive in helping us unravel some of these aspects. However, much remains to be discovered, requiring continued interrogation by the research community. In contrast to the situation for many neurological disorders, PD benefits from of a wide range of available animal models (pharmacological, toxin, genetic and alpha-synuclein) but this makes selection of the optimal one for a given study difficult. This is especially so when a study demands a model that displays a specific combination of features. While many excellent reviews of animal models already exist, this review takes a different approach with the intention of more readily informing this decision-making process. We have considered each feature of PD in turn - aetiology, pathology, pathogenesis, motor dysfunctions and non-motor symptoms - highlighting those animal models that replicate each. By compiling easily accessible tables and figures, we aim to provide the reader with a simple, go-to resource for selecting the optimal animal model of PD to suit their research needs.

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CuNA: Cumulant-based Network Analysis of genotype-phenotype associations in Parkinson's Disease

10.1101/2021.08.02.21261457 ◽

2021 ◽

Author(s):

Aritra Bose ◽

Daniel E. Platt ◽

Niina Haiminen ◽

LAXMI PARIDA

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Network Analysis ◽

Dopaminergic Neurons ◽

Rating Scales ◽

Clinical Phenotype ◽

Motor Symptoms ◽

Rna Seq ◽

Phenotype Data ◽

Non Motor Symptoms

Parkinson's Disease (PD) is a progressive neurodegenerative movement disorder characterized by loss of striatal dopaminergic neurons. Progression of PD is usually captured by a host of clinical features represented in different rating scales. PD diagnosis is associated with a broad spectrum of non-motor symptoms such as depression, sleep disorder as well as motor symptoms such as movement impairment, etc. The variability within the clinical phenotype of PD makes detection of the genes associated with early onset PD a difficult task. To address this issue, we developed CuNA, a cumulant-based network analysis algorithm that creates a network from higher-order relationships between eQTLs and phenotypes as captured by cumulants. We also designed a multi-omics simulator, CuNAsim to test CuNA's qualitative accuracy. CuNA accurately detects communities of clinical phenotypes and finds genes associated with them. When applied on PD data, we find previously unreported genes INPP5J, SAMD1 and OR4K13 associated with symptoms of PD affecting the kidney, muscles and olfaction. CuNA provides a framework to integrate and analyze RNA-seq, genotype and clinical phenotype data from complex diseases for more targeted diagnostic and therapeutic solutions in personalized medicine. CuNA and CuNAsim binaries are available upon request.

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Parkinson’s disease and translational research

Translational Neurodegeneration ◽

10.1186/s40035-020-00223-0 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Elisabeth Dinter ◽

Theodora Saridaki ◽

Leonie Diederichs ◽

Heinz Reichmann ◽

Björn H. Falkenburger

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Translational Research ◽

Dopaminergic Neurons ◽

Therapeutic Options ◽

Motor Symptoms ◽

New Approaches ◽

Biological Phenomena ◽

Non Motor Symptoms

AbstractParkinson’s disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.

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α-Synuclein in Parkinson’s Disease: Does a Prion-Like Mechanism of Propagation from Periphery to the Brain Play a Role?

The Neuroscientist ◽

10.1177/1073858420943180 ◽

2020 ◽

pp. 107385842094318

Author(s):

Huimin Zheng ◽

Changhe Shi ◽

Haiyang Luo ◽

Liyuan Fan ◽

Zhihua Yang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Lewy Bodies ◽

Cellular Level ◽

Motor Symptoms ◽

Lewy Neurites ◽

Growing Body ◽

Non Motor Symptoms ◽

The Brain

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases, defined as motor and non-motor symptoms associated with the loss of dopaminergic neurons and a decreased release of dopamine (DA). Currently, PD patients are believed to have a neuropathological basis denoted by the presence of Lewy bodies (LBs) or Lewy neurites (LNs), which mostly comprise α-synuclein (α-syn) inclusions. Remarkably, there is a growing body of evidence indicating that the inclusions undergo template-directed aggregation and propagation via template-directed among the brain and peripheral organs, mainly in a prion-like manner. Interestingly, some studies reported that an integral loop was reminiscent of the mechanism of Parkinson’s disease, denoting that α-syn as prionoid was transmitted from the periphery to the brain via specific pathways. Also the systematic life cycle of α-syn in the cellular level is illustrated. In this review, we critically assess landmark evidence in the field of Parkinson’s disease with a focus on the genesis and prion-like propagation of the α-syn pathology. The anatomical and cell-to-cell evidences are discussed to depict the theory behind the propagation and transferred pathways. Furthermore, we highlight effective therapeutic perspectives and clinical trials targeting prion-like mechanisms. Major controversies surrounding this topic are also discussed.

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Non-motor symptoms in clinical picture of the Parkinson’s disease

INTERNATIONAL NEUROLOGICAL JOURNAL ◽

10.22141/2224-0713.1.87.2017.96538 ◽

2017 ◽

Vol 0 (1.87) ◽

pp. 58-63

Author(s):

I.N. Karaban ◽

O.V. Shalenko ◽

S.A. Kryzhanovskiy

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Picture ◽

Motor Symptoms ◽

Non Motor Symptoms

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The Parkinson’s Real-World Impact Assessment (PRISM) Study: A European Survey of the Burden of Parkinson’s Disease in Patients and their Carers

Journal of Parkinson s Disease ◽

10.3233/jpd-212611 ◽

2021 ◽

pp. 1-15

Author(s):

Eduardo Tolosa ◽

Georg Ebersbach ◽

Joaquim J. Ferreira ◽

Olivier Rascol ◽

Angelo Antonini ◽

...

Keyword(s):

Quality Of Life ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Impact Assessment ◽

Real World ◽

European Countries ◽

Life Questionnaire ◽

Motor Symptoms ◽

Non Motor Symptoms

Background: A greater understanding of the everyday experiences of people with Parkinson’s disease (PD) and their carers may help improve clinical practice. Objective: The Parkinson’s Real-world Impact assesSMent (PRISM) study evaluated medication use, health-related quality of life (HRQoL) and the use of healthcare resources by people with PD and their carers. Methods: PRISM is an observational cross-sectional study, in which people with PD and their carers completed an online survey using structured questionnaires, including the Parkinson’s Disease Quality of Life Questionnaire (PDQ-39), Non-Motor Symptoms Questionnaire (NMSQuest) and Zarit Burden Interview (ZBI). Results: Data were collected from 861 people with PD (mean age, 65.0 years; mean disease duration, 7.7 years) and 256 carers from six European countries. People with PD reported a large number of different co-morbidities, non-motor symptoms (mean NMSQuest score, 12.8), and impaired HRQoL (median PDQ-39 summary score, 29.1). Forty-five percent of people with PD reported at least one impulse control behaviour. Treatment patterns varied considerably between different European countries. Levodopa was taken in the last 12 months by 85.9% of participants, and as monotherapy by 21.8% . Carers, who were mostly female (64.8%) and the partner/spouse of the person with PD (82.1%), reported mild to moderate burden (mean ZBI total score, 26.6). Conclusions: The PRISM study sheds light on the lives of people with PD and those who care for them, re-emphasising the many challenges they face in everyday life. The study also provides insights into the current treatment of PD in Europe.

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Study of cognitive impairment and genetic polymorphism of SLC41A1 (rs11240569 allele) in Parkinson’s disease in Upper Egypt: case-control study

The Egyptian Journal of Neurology Psychiatry and Neurosurgery ◽

10.1186/s41983-021-00341-0 ◽

2021 ◽

Vol 57 (1) ◽

Author(s):

Hamdy N. El-Tallawy ◽

Tahia H. Saleem ◽

Wafaa M. Farghaly ◽

Heba Mohamed Saad Eldien ◽

Ashraf Khodaery ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cognitive Impairment ◽

Case Control Study ◽

Case Control ◽

Control Group ◽

Motor Symptoms ◽

And Control ◽

Non Motor Symptoms ◽

Control Study

Abstract Background Parkinson’s disease is one of the neurodegenerative disorders that is caused by genetic and environmental factors or interaction between them. Solute carrier family 41 member 1 within the PARK16 locus has been reported to be associated with Parkinson’s disease. Cognitive impairment is one of the non-motor symptoms that is considered a challenge in Parkinson’s disease patients. This study aimed to investigate the association of rs11240569 polymorphism; a synonymous coding variant in SLC41A1 in Parkinson’s disease patients in addition to the assessment of cognitive impairment in those patients. Results In a case -control study, rs11240569 single nucleotide polymorphisms in SLC41A1, genes were genotyped in 48 Parkinson’s disease patients and 48 controls. Motor and non-motor performance in Parkinson's disease patients were assessed by using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The genotype and allele frequencies were compared between the two groups and revealed no significant differences between case and control groups for rs11240569 in SLC41A1 gene with P value .523 and .54, respectively. Cognition was evaluated and showed the mean ± standard deviation (SD) of WAIS score of PD patients 80.4 ± 9.13 and the range was from 61 to 105, in addition to MMSE that showed mean ± SD 21.96 ± 3.8. Conclusion Genetic testing of the present study showed that rs11240569 polymorphism of SLC41A1 gene has no significant differences in distributions of alleles and genotypes between cases and control group, in addition to cognitive impairment that is present in a large proportion of PD patients and in addition to the strong correlation between cognitive impairment and motor and non-motor symptoms progression.

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α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

npj Parkinson s Disease ◽

10.1038/s41531-021-00210-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Abeer Dagra ◽

Douglas R. Miller ◽

Min Lin ◽

Adithya Gopinath ◽

Fatemeh Shaerzadeh ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Activity ◽

Dopaminergic Neurons ◽

Prolonged Exposure ◽

D2 Receptor ◽

Neuronal Firing ◽

Dopamine Neurons ◽

Loss Of Function ◽

Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

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Weeding through the haze: a survey on cannabis use among people living with Parkinson’s disease in the US

npj Parkinson s Disease ◽

10.1038/s41531-021-00165-y ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Megan P. Feeney ◽

Danny Bega ◽

Benzi M. Kluger ◽

A. Jon Stoessl ◽

Christiana M. Evers ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Scientific Evidence ◽

Symptom Control ◽

Cannabis Use ◽

Symptom Improvement ◽

Motor Symptoms ◽

The Us ◽

Alternative Means ◽

Non Motor Symptoms

AbstractSymptomatic management of Parkinson’s disease (PD) is complex and many symptoms, especially non-motor symptoms, are not effectively addressed with current medications. In the US, cannabis has become more widely available for medical and recreational use, permitting those in the PD community to try alternative means of symptom control. However, little is known about the attitudes towards, and experiences with, cannabis use among those living with PD. To address this shortcoming, we distributed an anonymous survey to 7,607 people with PD in January 2020 and received 1339 responses (17.6%). 1064 complete responses were available for analysis. Respondents represented 49 states with a mean age of 71.2 years (±8.3) and mean PD duration of 7.4 years (±6.2). About a quarter of respondents (24.5%) reported cannabis use within the previous six months. Age and gender were found to be predictors of cannabis use in this sample (Age OR = 0.95, 95% CI 0.93 to 0.97; Male OR = 1.44, 95% CI 1.03 to 2.03). Users reported learning about cannabis use from the internet/news (30.5%) and friends or other people with PD (26.0%). Cannabis users were more likely to report insufficient control of their non-motor symptoms with prescription medications than non-users (p = 0.03). Cannabis was primarily used for PD (63.6%) and was most often used to treat nonmotor symptoms of anxiety (45.5%), pain (44.0%), and sleep disorders (44.0%). However, nearly a quarter of users (23.0%) also reported they had stopped cannabis use in the previous six months, primarily due to a lack of symptom improvement (35.5%). Three quarters of respondents (75.5%) did not use cannabis, primarily because there was a lack of scientific evidence supporting efficacy (59.9%). Our results suggest that the lack of formal guidance or research evidence about cannabis for PD may in part underlie inconsistencies in both use and reported effectiveness.

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