Parkinson's disease (PD) is characterized by rigidity symptoms that extend motoric symptoms, including cognitive rigidity (e.g., reduced cognitive set-shifting) and "rigid" personality (e.g., reduced novelty-seeking). These non-motor symptoms have been associated with fronto-striatal dysfunction in this disorder. Disruption of fronto-parietal attentional networks in PD suggests rigidity may extend to perception. To examine perceptual rigidity, non-demented individuals with mild-moderate PD (16-27/experiment), matched normal control (NC; 15-25/experiment) and young control adults (YC; 17-22/experiment) were presented with bistable images. Study 1 examined perceptual flexibility in normal aging. The Necker cube, a bistable image that can be perceived as having the upper-left or lower-right face in front, was presented under passive-viewing and two volitional-control conditions: hold one percept in front, and switch between the two percepts. Under passive viewing, dominance durations (time spent on each percept) were shorter in YC than NC. Relative to YC, NC were less able to increase dominance durations in the hold condition but were comparable in the switch condition. Study 2 applied the Necker-cube experiment to PD and extended it to passive viewing during binocular rivalry. Inconsistently with our hypotheses, PD showed comparable dominance durations to NC in the passive viewing – Necker cube, while demonstrating shorter dominance durations (equivalent to faster perceptual alternation) during binocular rivalry. Relative to passive viewing, PD showed a trend toward less ability than NC to increase dominance durations in the Hold condition, and were significantly less able than NC to reduce dominance durations in the Switch condition, both results indicative of perceptual rigidity. Dominance durations on passive viewing correlated with personality (novelty-seeking) in PD, and not with cognitive rigidity in either group. Study 3 examined whether enhancement of low-level visual cues would reduce perceptual rigidity in PD. Low level cues helped both PD and NC to exert better control over the conditions they did not demonstrate difficulties in Study 1 and Study 2. These results suggest that perceptual rigidity occurs in mild-moderate PD. The provision of cues, however, does not compensate for this rigidity. Finally, these results further suggest an association in PD between novelty-seeking and the ability to explore the perceptually ambiguous world. / 2017-11-18T00:00:00Z

Parkinson's disease (PD) is one of the most common neurodegenerative diseases characterized by cell death in the substantia nigra pars compacta (SNpc) and the appearance of aggregated α-synuclein (α-syn). Autophagosomes accumulation and lysosomal reduction were discovered in PD patients' brain, which indicated the deficiency of autophagy in the progress of PD. TFEB (transcription factor EB) is a member of basic helix -loop-helix-leucine-zipper transcription factors (MiT family) and is a key master monitor for autophagy and lysosome biogenesis. Overexpression of TFEB is able to rescue the dopaminergic neurons (DAs) loss and α-syn aggregated in α-syn transgenic mice model and MPTP PD model. Hence, in recent years, many researchers have considered TFEB as a new therapeutic target for PD In this study, we discovered a novel TFEB activator named E4 by screening synthesized curcumin analogs. We have found that E4 strongly promoted TFEB nuclear translocation and induced autophagy in different cell lines. TFEB is essential for E4-induced autophagy flux. We also demonstrated that the underlying mechanism of E4 activate TFEB is mainly through inhibiting mTORC1 activity. We constitutively activate mTOR by knockdown TSC2 abrogated the increase of LC3-II and decrease of p-TFEB. We further estimated the protective effects of E4 in overexpressed α-syn model and neurotoxins induced cytotoxicity model. Treated with E4 for 48h in N2a transfected with A53T α-synuclein cells dose-dependently reduce the α-synuclein level. At the same time, we established the MPP+ model in PC12 cells which is pre-treated cell with E4 for 6 hours and then co-treated cells with MPP+ for 48 hours. The cell viability results showed that E4 significantly protect PC12 cells against MPP+ cytotoxicity dose-dependently. E4 had shown good neuroprotective effects in PD in vitro models while poor water solubility and low brain permeability restricted its application in PD animal models. Hence, assembling E4 molecules into self-carried nanoparticles (NanoE4) addressed the issue of poor water solubility and intranasal administration solved the problem of low permeability. In order to track NanoE4 release in vitro and in vivo, we further investigated the absorption and emission of NanoE4. However, the absorption fluorescence results showed that NanoE4 exhibits the strong aggregation-caused quenching effect (ACQ) due to π-π stacking of the planar molecule within the NPs. NanoE4 have much weak emission compared with E4 molecules. Therefore, we fabricated E4-TPAAQ NPs by co-reprecipitating E4 molecules with the reported fluorescent organic compound TPAAQ (2,6-Bis[4-(diphenylamino) phenyl] anthraquinone). Next, we developed an intranasal drug delivery system in our lab. After intranasal co-drop nanodrug E4-TPAAQ NPs for 24 hours, we observed strong fluorescence distributed in the brain which indicated that deliver nanoparticles into the brain successfully through nasal-brain system. Therefore, we examined the protective effect of NanoE4 in MPTP-induced PD mice model. In MPTP models, we found autophagy dysfunction, motor function decrease and increase of α-synuclein as reported previously. Treatment with NanoE4 rescued the motor dysfunction induced by MPTP. NanoE4 also increase TH level in the striatum part of midbrain. NanoE4 treatment also decreased the α-synuclein protein aggregate in both SNpc and striatum. Overall, these results demonstrate the neuroprotection NanoE4 against PD. Collectively, our findings 1) discovered a novel TFEB activator E4 that inhibited the mTOR pathway 2) indicated in vitro and in vivo experimental evidence for TFEB activator as the anti-PD drug candidate 3) provide a novel drug develop and delivery system for potential PD that limited by water solubility and BBB (blood-brain barrier) obstacle

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, featuring motor signs such as tremors, bradykinesia, and impaired gait that are often preceded by nonmotor symptoms such as anxiety/depression and olfactory dysfunction. Interestingly, significant olfactory loss was found to be manifested in the majority of PD patients and may precede motor symptoms by years, and thus can be used for the risk assessment of developing PD in asymptomatic individuals. The main pathological feature of PD is the progressive and irreversible loss of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain. Although the detailed etiology of PD remains unclear, most PD cases were found to be sporadic and can be associated with environmental factors. Only 5–10% of patients result from familial PD. With considerable effort in the past two decades, a number of genes associated with familial PD have been identified and interestingly, many of these genes are involved in regulating and maintaining mitochondrial function. The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The PARL gene product is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrial proteins involved in mitochondrial morphology, apoptosis, and mitophagy. To date, functional and genetic studies of PARL have been mainly performed in mammals. However, little is known about PARL function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two PARL paralogs: parla and parlb. Here, we show novel information concerning the role of PARL in zebrafish by establishing a loss-of-function mutation in parla and parlb via CRISPR/Cas9- mediated mutagenesis. We examined DA neuron numbers in the adult brain and expression of genes associated with DA neuron function in larvae and adults. We show that loss of parla function, as well as loss of both parla and parlb function result in loss of DA neurons in the olfactory bulb and telencephalon of adult zebrafish brain. Changes in the levels of tyrosine hydroxylase transcripts supported this neuronal loss. Expression of fis1, a gene involved in mitochondrial fission, was increased in parla mutants and in fish with loss of parla and parlb function. Furthermore, we showed that loss of parla and/or parlb function translates into altered locomotion parameters and that loss of parla but not parlb function results in impaired olfaction. Finally, increased susceptibility to neurotoxin exposure was identified in mutants with loss of both parla and parlb function but not with loss of parla or parlb function. These results suggest an evident role for parla in the development and/or maintenance of DA neuron function in zebrafish and confirm the existence of redundant and non-redundant functions for the two paralogs, parla and parlb.

We investigated the association of Bell's palsy (BP) with the subsequent risk of Parkinson's disease (PD) using a case-control study design. We matched 196 incident cases of PD in Olmsted County, MN, to 196 general population controls with same age (±1 year) and sex, and we reviewed the complete medical records of cases and controls in a medical records-linkage system to detect BP. Six of the 196 patients with PD and none of the 196 controls were diagnosed with BP before PD (exact binomial probability, P = 0.02). The median age at occurrence of BP was 49.5 years (range, 15-84 years) and the median time between BP and the onset of PD was 27.5 years (range, 2-54 years). The findings were similar using a standardized incidence ratio (SIR) approach, but were not statistically significant. This initial association between BP and PD awaits replication.

Summary. Despite its being the most efficacious drug for symptom reversal in Parkinson's disease (PD), there is concern that chronic levodopa (L-DOPA) treatment may be detrimental. In this paper we review the potential for L-DOPA to 1) autoxidize from a catechol to a quinone, and 2) generate other reactive oxygen species (ROS). Overt toxicity and neuroprotective effects of L-DOPA, both in vivo and in vitro, are described in the context of whether L-DOPA may accelerate or delay progression of human Parkinson's disease.

Epidemiological studies implicate pesticide exposure as a possible etiologic factor in idiopathic Parkinson's Disease, which results from degeneration of nigrostriatal neurons, along with reduced levels of the neurotransmitter, dopamine. Behavioral and neurochemical analyses in C57BL6 mice were performed following a subchronic dosing regime with the organochlorine insecticide heptachlor or the pyrethroid deltamethrin. Results were compared to those induced by the established parkinsonian neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). At the end of the treatment period, mice were assessed for effects on behavior, as well as levels of striatal dopamine, nerve terminal respiration, and synaptosomal dopamine transport. The primary behavioral effect of deltamethrin was incoordination, while heptachlor caused hyperexcitability and increased locomotion. The major neurochemical effect observed for both compounds was upregulation of the presynaptic dopamine transporter (DAT) by 70% and 100% for deltamethrin and heptachlor, respectively. The insecticides exerted only modest effects on striatal levels of dopamine and its metabolite, dihydroxyphenylacetic acid. However, doses of heptachlor higher than those which caused induction of DAT (e.g. greater than or equal to 25 mg/kg), when administered subchronically, were found to cause convulsions in some animals and caused marked, dose-dependent depression of basal striatal tissue respiration rates. No synergism was observed between the effects of insecticides and MPTP. Enhanced transport was thought to be a compensatory effect from increased release of transmitters by the insecticides, <i>in vivo</i>. Striatal dopamine, GABA and glutamate nerve terminals were differentially sensitive to the releasing effects of heptachlor compared to cortical serotonin terminals, and responded in the following rank order of sensitivity: dopamine > GABA > glutamate > serotonin. Additional experiments to characterize the mechanism(s) by which cyclodienes facilitate release of neurotransmitters in synaptosomes demonstrated a lack of distinct Ca²⁺ component and no involvement of retrograde DAT activity, suggesting that released label was of vesicular origin, but did not require Ca²⁺. Insecticidal toxicants, such as organochlorines and pyrethroids, which augment dopamine release and increase the maximal rate of dopamine uptake, may inundate the cytosol of nigrostriatal neurons with high concentrations of free dopamine, which has been shown by other researchers to induce apoptosis and may thereby contribute to the development of Parkinson's disease. Funding for this work was provided under grant number HHHREP 94-01 by the Hawaii Heptachlor Foundation, a non-profit organization. The Hawaii Heptachlor Foundation may be contacted at the following address: Ocean View Center PH#3, 707 Richards St., Honolulu, HI 96813. / Ph. D.

No description available.

Parkinson's disease is a chronic neurological disorder affecting hundreds of thousands of Americans. The current best practice for assessment of this disease is a clinical examination and subjective rating using the Unified Parkinson's Disease Rating Scale. Such ratings are coarse scaled, subject to rater bias, and costly. Instruments which provide objective measurements of disease state can eliminate rater bias, provide repeatable data, and increase the frequency and responsiveness of subject assessments, expediting the validation of new therapies and treatments. This thesis describes the design and implementation of a battery of bio-mechanical devices suitable for clinical and in home use, including descriptions of the instruments and the functionality of the data acquisition software, as well as the overall system used for data collection. A data analysis algorithm is fully described, and descriptive statistics of pilot data from twenty two subjects are reported. These statistics show promising correlations of time duration metrics with the motor subsection of the UPDRS, as well as good responsiveness to dopaminergic intervention. Data also suggests that these devices have an advantage over previously described devices in the ability to record the full range of motion in standard assessment tasks, thereby providing additional metrics related to hesitations and halts in prescribed movements.

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Parkinson's disease (PD), the second most common neurodegenerative disorder after Alzheimer's disease, is one of the leading disability disorders with about 10 million people affected worldwide. The pathological hallmarks of PD are defined by the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain with its characteristic clinical motor and non-motor symptoms. However, the loss in dopaminergic neurons causes characteristic clinical manifestations, which include non-motor and motor symptoms. Damage to cholinergic neurotransmitter systems causes non-motor symptoms like sleeping disorders, depression, and a variety of other psychiatric issues, while a malfunctioning nigrostriatal dopaminergic pathway causes such motor symptoms as tremors, stiffness, and postural instability. PD symptoms usually mirror the degree of alteration to neuronal integrity in the affected parts of the brain, but the severity of progression varies with each patient.

>Magister Scientiae - MSc / Parkinson’s disease (PD) is a neurodegenerative disorder that occurs due to a loss of dopaminergic neurons in the substantia nigra. It is one of the most common neurodegenerative disorders, ranking second only to Alzheimer’s disease. Research on the genetic causes of PD over the past two decades has led to the discovery of several PD-associated genes. Currently, researchers have identified 23 genes that are linked to rare monogenic forms of PD with Mendelian inheritance. In sub-Saharan Africa (SSA), PD has received little attention due to factors such as underfunded healthcare infrastructure, the absence of epidemiological data, and a scarcity of neurologists. In the relatively few published studies, it has been shown that the known PD mutations play a minor role in disease etiology in SSA populations. In the current study, we follow up on previous work done in an MMed study investigating a South African family with several family members (mother and three sons) suffering from PD. / 2023