Etiology Of Parkinson's Disease Research Articles

Multiple-Hit Hypothesis in Parkinson's Disease: LRRK2 and Inflammation.

The multiple hit hypothesis for Parkinson’s disease (PD) suggests that an interaction between multiple (genetic and/or environmental) risk factors is needed to trigger the pathology. Leucine-Rich Repeat Kinase 2 (LRRK2) is an interesting protein to study in this context and is the focus of this review. More than 15 years of intensive research have identified several cellular pathways in which LRRK2 is involved, yet its exact physiological role or contribution to PD is not completely understood. Pathogenic mutations in LRRK2 are the most common genetic cause of PD but most likely require additional triggers to develop PD, as suggested by the reduced penetrance of the LRRK2 G2019S mutation. LRRK2 expression is high in immune cells such as monocytes, neutrophils, or dendritic cells, compared to neurons or glial cells and evidence for a role of LRRK2 in the immune system is emerging. This has led to the hypothesis that an inflammatory trigger is needed for pathogenic LRRK2 mutations to induce a PD phenotype. In this review, we will discuss the link between LRRK2 and inflammation and how this could play an active role in PD etiology.

Mitochondrial Homeostasis and Signaling in Parkinson's Disease.

The loss of dopaminergic (DA) neurons in the substantia nigra leads to a progressive, long-term decline of movement and other non-motor deficits. The symptoms of Parkinson’s disease (PD) often appear later in the course of the disease, when most of the functional dopaminergic neurons have been lost. The late onset of the disease, the severity of the illness, and its impact on the global health system demand earlier diagnosis and better targeted therapy. PD etiology and pathogenesis are largely unknown. There are mutations in genes that have been linked to PD and, from these complex phenotypes, mitochondrial dysfunction emerged as central in the pathogenesis and evolution of PD. In fact, several PD-associated genes negatively impact on mitochondria physiology, supporting the notion that dysregulation of mitochondrial signaling and homeostasis is pathogenically relevant. Derangement of mitochondrial homeostatic controls can lead to oxidative stress and neuronal cell death. Restoring deranged signaling cascades to and from mitochondria in PD neurons may then represent a viable opportunity to reset energy metabolism and delay the death of dopaminergic neurons. Here, we will highlight the relevance of dysfunctional mitochondrial homeostasis and signaling in PD, the molecular mechanisms involved, and potential therapeutic approaches to restore mitochondrial activities in damaged neurons.

Deficits in Motor Performance, Neurotransmitters and Synaptic Plasticity in Elderly and Experimental Parkinsonian Mice Lacking GPR37.

Parkinson’s disease (PD) etiology is attributed to aging and the progressive neurodegeneration of dopamine (DA) neurons of substantia nigra pars compacta (SNc). GPR37 is an orphan G-protein Coupled Receptor (GPCR) that is linked to the juvenile form of PD. In addition, misfolded GPR37 has been found in Lewy bodies. However, properly folded GPR37 found at the cell membrane appears to exert neuroprotection. In the present study we investigated the role of GPR37 in motor deficits due to aging or toxin-induced experimental parkinsonism. Elderly GPR37 knock out (KO) mice displayed hypolocomotion and worse fine movement performance compared to their WT counterparts. Striatal slice electrophysiology reveiled that GPR37 KO mice show profound decrease in long term potentiation (LTP) formation which is accompanied by an alteration in glutamate receptor subunit content. GPR37 KO animals exposed to intrastriatal 6-hydroxydopamine (6-OHDA) show poorer score in the behavioral cylinder test and more loss of the DA transporter (DAT) in striatum. The GPR37 KO striata exhibit a significant increase in GABA which is aggravated after DA depletion. Our data indicate that GPR37 KO mice have DA neuron deficit, enhanced striatal GABA levels and deficient corticostriatal LTP. They also respond stronger to 6-OHDA-induced neurotoxicity. Taken together, the data indicate that properly functional GPR37 may counteract aging processes and parkinsonism.

N-degron-mediated degradation and regulation of mitochondrial PINK1 kinase.

Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by a gradual loss of a specific group of dopaminergic neurons in the substantia nigra. Importantly, current treatments only address the symptoms of PD, yet not the underlying molecular causes. Concomitantly, the function of genes that cause inherited forms of PD point to mitochondrial dysfunction as a major contributor in the etiology of PD. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses including high levels of reactive oxygen species and protein misfolding, which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to identify, repair and/or eliminate abnormal dysfunctional mitochondria. One such mechanism is mitophagy, a process which involves PTEN-induced putative kinase 1 (PINK1), a mitochondrial Ser/Thr kinase and Parkin, an E3 ubiquitin ligase, each encoded by genes responsible for early-onset autosomal recessive familial PD. Over 100 loss-of-function mutations in the PTEN-induced putative kinase 1 (PINK1) gene have been reported to cause autosomal recessive early-onset PD. PINK1 acts upstream of Parkin and is essential for the mitochondrial localization and activation of Parkin. Upon mitochondrial damage, PINK1 builds up on the outer mitochondrial membrane (OMM) and mediates the activation of Parkin. Activated Parkin then ubiquitinates numerous OMM proteins, eliciting mitochondrial autophagy (mitophagy). As a result, damaged mitochondrial components can be selectively eliminated. Thus, PINK1 acts a sensor of damage via fine-tuning of its levels on mitochondria, where it activates Parkin to orchestrate the clearance of unhealthy mitochondria. Previous work has unveiled that the Arg-N-end rule degradation pathway (Arg-N-degron pathway) mediates the degradation of PINK1, and thus fine-tune PINK1-dependent mitochondrial quality control pathway. Herein, we briefly discuss the interconnection between N-end rule degradation pathways and mitophagy in the context of N-degron mediated degradation of mitochondrial kinase PINK1 and highlight some of the future prospects.

Vascular, flow and perfusion abnormalities in Parkinson's disease

BackgroundReduced flow into the brain or decreased jugular venous outflow from the brain may serve as a potential biomarker for Parkinson's disease (PD). Our goal was to compare the presence of vascular abnormalities, flow, and increases in midbrain iron content (a hallmark of the disease) in patients with PD. MethodsA total of 85 PD patients and 85 healthy controls (HCs) were imaged at 3T. We assessed vascular abnormalities using magnetic resonance (MR) venography, average cerebral blood flow using 2D flow quantification, and substantia nigra iron content using susceptibility mapping. ResultsFifty-two percent (52%) of the PD subjects showed venous structural and functional abnormalities in the two most severe categories, while ony 14% of the HC group showed these abnormalities. Total arterial flow (tA) was significantly lower for the PD group (10.9 ± 1.8 ml/s) compared to the HCs (11.6 ± 2.1 ml/s) (t = 2.28, p = 0.02). Of the PD patients (HCs), 42% (14%) had little flow on the left side. PD patients had higher heart rates and lower perfusion and the lower perfusion correlated with increased iron content in the substantia nigra. ConclusionSome PD patients showed abnormal left internal jugular veins, lower tA, higher heart rates, and lower perfusion relative to HCs. These indicators could serve as early biomarkers for PD and create new avenues for future studies regarding the etiology of PD.

DNA damage and repair in Parkinson's disease: Recent advances and new opportunities.

Parkinson's disease (PD) is the most common movement neurodegenerative disorder. Although our understanding of the underlying mechanisms of pathogenesis in PD has greatly expanded, this knowledge thus far has failed to translate into disease-modifying therapies. Therefore, it is of the utmost urgency to interrogate further the multifactorial etiology of PD. DNA repair defects cause many neurodegenerative diseases. An exciting new PD research avenue is the role that DNA damage and repair may play in neuronal death. The goal of this mini-review was to discuss the evidence for the types of DNA damage that accumulates in PD, which has provided clues for which DNA repair pathways, such as DNA double-strand break repair, are dysfunctional. We further highlight compelling data for activation of the DNA damage response in familial and idiopathic PD. The significance of DNA damage and repair is emerging in the PD field and linking these insights to PD pathogenesis may provide new insights into PD pathophysiology and consequently lead to new therapies.

Autophagy and Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by motor system dysfunction. The etiology of PD has been linked with aging, environmental toxins and genetic mutation, while molecular pathogenesis of PD includes various factors, such as impaired protein homeostasis, oxidative stress, mitochondria dysfunction, synaptic transmission impairment, calcium homeostasis imbalance, prion-like α-synuclein transmission and neuron inflammation. Autophagy is a conserved bulk degradation process to maintain cellular homeostasis. Impairment of autophagy has been reported to be involved in the pathogenesis of PD. Coding proteins of several PD-related genes, such as SNCA, LRRK2, GBA, ATP13A2, VPS35 and FBXO7, are implicated in or affected by autophagy process. Furthermore, various pathogenic events during PD directly or indirectly interfere with the autophagy pathway, and dysregulation of autophagy has been observed in different neurotoxic PD models. Autophagy has been regarded as a potential therapeutic target for PD treatment. Indeed, modulations of autophagy-regulated genes (BECN1 and TFEB) expression exerted neuroprotection against PD models, and various autophagy regulators, such as rapamycin, trehalose, lysosome modulators and other small molecule autophagy inducers, have displayed neuroprotective effects in experimental PD models. Taken together, autophagy dysfunction has been implicated in the pathogenesis of PD, and pharmacological modulation of autophagy may be a new therapeutic strategy for the PD treatment.

Exercise and Parkinson's Disease.

Parkinson's disease (PD) is an aging-related neurodegenerative disorder characterized by progressive motor impairment.The etiology of PD is poorly understood but likely involves both genetic and environmental factors; the management of the disease is still with symptomatic therapy without any interference on the progression of neurodegeneration. In the past two decades, the results of a series of prospective cohort studies suggested that lifestyle factors likely modify the risk of developing PD. Among these, physical activity is known to reduce the risk of a wide range of diseases and conditions, including cardiovascular disease, stroke, and diabetes.Recently, a growing body of evidence has suggested that increased physical activity may also reduce the risk of PD and partly improve motor and non-motor symptoms during the disease course.Here we report the main findings on the effect of physical activity on both mobility and cognition either in animal models of PD or in people with PD. We also highlighted the structural and functional links between gait and cognition by reporting evidence from neuroimaging studies.

Pathways of protein synthesis and degradation in PD pathogenesis.

Since the discovery of protein aggregates in the brains of individuals with Parkinson's disease (PD) in the early 20th century, the scientific community has been interested in the role of dysfunctional protein metabolism in PD etiology. Recent advances in the field have implicated defective protein handling underlying PD through genetic, in vitro, and in vivo studies incorporating many disease models alongside neuropathological evidence. Here, we discuss the existing body of research focused on understanding cellular pathways of protein synthesis and degradation, and how aberrations in either system could engender PD pathology with special attention to α-synuclein-related consequences. We consider transcription, translation, and post-translational modification to constitute protein synthesis, and protein degradation to encompass proteasome-, lysosome- and endoplasmic reticulum-dependent mechanisms. Novel findings connecting each of these steps in protein metabolism to development of PD indicate that deregulation of protein production and turnover remains an exciting area in PD research.

Neuroprotective function of Omi to α-synuclein-induced neurotoxicity

The main pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies, which mainly consist of aggregated α-synuclein. Based on the neurotoxicity of oligomeric α-synuclein and its significance in the aetiology of PD, there has been decades of effort to elucidate an enzyme specifically degrading oligomeric α-synuclein. Here we report an enzyme, Omi, which specifically recognizes and precisely degrades oligomeric α-synuclein but not monomeric α-synuclein. After enzymatic and functional analyses of Omi in in vitro, we developed an in vivo assay system of dual gene interaction in Drosophila to investigate further the etiological role of Omi in PD. Pan-neuronal expression of Omi rescued Parkinsonism in a Drosophila model of PD, while Knockout of Omi exacerbated Parkinsonism. Expression of Omi counteracted the α-synuclein-induced retinal degeneration, providing additional evidence for Omi's protective role oligomeric α-synuclein. This work reports identification of the catabolic pathway of oligomeric α-synuclein as well as showing how Omi functions as the key molecule in the recognition and degradation of toxic oligomeric α-synuclein, a possible cause of neurodegeneration in PD, without affecting monomeric α-synuclein which is a native essential molecule for the normal function of neurons.

Dopamine Genetics: Substance Use Disorders vs. Parkinson’s Disease

It is established that Substance use disorders (SUDs) and Parkinson’s Disease (PD) among many other neuropsychiatric disorders are dopamine (DA)-related brain disorders with strong heritability. However, it is unclear whether DA-associated genetic risks share commonality across these disorders. This study utilizes the Genotype and Phenotype Database (dbGaP), by downloading related genome-wide association studies (GWAS) for individual genotype/phenotypes. According to our results DA pathways are significantly implicated in the genetic etiology of both SUDs and PD but much more in the former. Epistatic effects may represent a major portion of missing heritability observed in current main effect-oriented GWAS analyses.

Bacterial Metabolites Mirror Altered Gut Microbiota Composition in Patients with Parkinson's Disease.

Increasing evidence is supporting the hypothesis of α-synuclein pathology spreading from the gut to the brain although the exact etiology of Parkinson’s disease (PD) is unknown. Furthermore, it has been proposed that inflammation, via the gastrointestinal tract, potentially through infections, may contribute to α-synuclein pathogenesis, and thus to the risk of developing PD. Recently, many studies have shown that PD patients have an altered microbiota composition compared to healthy controls. Inflammation in the gut might drive microbiota alterations or vice versa. Many studies focused on the detection of biomarkers of the etiology, onset, or progression of PD however also report metabolites from bacterial origin. These metabolites might reflect the bacterial composition and as well play an important role in immune homeostasis, ultimately affecting the progression of PD. Besides the bacterial metabolites, pharmacological treatment of PD might play a crucial role during the progression and thus treatment of the disease on the immune system. This review aims to establish a link between the microbial composition with the observed alterations of bacterial metabolites and their impact on the immune system, which could have influential effect in onset, progression and etiology of PD.

Research-based Updates in Swallowing and Communication Dysfunction in Parkinson Disease: Implications for Evaluation and Management.

Individuals with Parkinson disease (PD) present with complex and variable symptoms, with recent findings suggesting that the etiology of PD extends beyond the involvement of just the basal ganglia. These symptoms include significant impairments in the speech and swallowing domains, which can greatly affect quality of life and therefore require therapeutic attention. This research-based update reviews the neurophysiological basis for swallowing and speech changes in PD, the effectiveness of various types of treatments, and implications for symptom evaluation and management. The mechanisms responsible for swallowing and speech symptoms in PD remain largely unknown. Dopaminergic medication and deep-brain-stimulation do not provide consistent benefits for these symptoms suggesting a non-dopaminergic network is involved. Importantly, evidence suggests that symptoms of dysphagia and hypokinetic dysarthria may be early indications of PD, so it is critical to investigate the cause of these changes.

Mutations in CHCHD2 cause α-synuclein aggregation.

Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson's disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields α-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes α-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble α-synuclein aggregates, the extent of which was comparable to that of a case with α-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of α-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. α-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic α-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by α-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines α-synuclein stability in the etiology of PD.

New Insights on the Role of Manganese in Alzheimer's Disease and Parkinson's Disease.

Manganese (Mn) is an essential trace element that is naturally found in the environment and is necessary as a cofactor for many enzymes and is important in several physiological processes that support development, growth, and neuronal function. However, overexposure to Mn may induce neurotoxicity and may contribute to the development of Alzheimer’s disease (AD) and Parkinson’s disease (PD). The present review aims to provide new insights into the involvement of Mn in the etiology of AD and PD. Here, we discuss the critical role of Mn in the etiology of these disorders and provide a summary of the proposed mechanisms underlying Mn-induced neurodegeneration. In addition, we review some new therapy options for AD and PD related to Mn overload.

Intracellular and Intercellular Mitochondrial Dynamics in Parkinson's Disease.

The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson’s disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration. As calcium binding to alpha-synuclein is one of the important triggers of alpha-synuclein aggregation, mitochondrial dysfunction will promote inclusion body formation and disease progression. Increased reactive oxygen species (ROS) resulting from inefficiencies in the electron transport chain also contribute to the formation of alpha-synuclein aggregates and neuronal loss. Recent studies have also highlighted defects in mitochondrial clearance that lead to the accumulation of depolarized mitochondria. Transaxonal and intracytoplasmic translocation of mitochondria along the microtubule cytoskeleton may also be affected in diseased neurons. Furthermore, nanotube-mediated intercellular transfer of mitochondria has recently been reported between different cell types and may have relevance to the spread of PD pathology between adjacent brain regions. In the current review, the contributions of both intracellular and intercellular mitochondrial dynamics to the etiology of PD will be discussed.

Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade.

MicroRNAs (miRs) downregulate or upregulate the mRNA level by binding to the 3′-untranslated region (3′UTR) of target gene. Dysregulated miR levels can be used as biomarkers of Parkinson’s disease (PD) and could participate in the etiology of PD. In the present study, 45 brain-enriched miRs were evaluated in serum samples from 50 normal subjects and 50 sporadic PD patients. The level of miR-204-5p was upregulated in serum samples from PD patients. An upregulated level of miR-204-5p was also observed in the serum and substantia nigra (SN) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Expression of miR-204-5p increased the level of α-synuclein (α-Syn), phosphorylated (phospho)-α-Syn, tau, or phospho-tau protein and resulted in the activation of endoplasmic reticulum (ER) stress in SH-SY5Y dopaminergic cells. Expression of miR-204-5p caused autophagy impairment and activation of c-Jun N-terminal kinase (JNK)-mediated apoptotic cascade in SH-SY5Y dopaminergic cells. Our study using the bioinformatic method and dual-luciferase reporter analysis suggests that miR-204-5p positively regulates mRNA expression of dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) by directly interacting with 3′UTR of DYRK1A. The mRNA and protein levels of DYRK1A were increased in SH-SY5Y dopaminergic cells expressing miR-204-5p and SN of MPTP-induced PD mouse model. Knockdown of DYRK1A expression or treatment of the DYRK1A inhibitor harmine attenuated miR-204-5p-induced increase in protein expression of phospho-α-Syn or phospho-tau, ER stress, autophagy impairment, and activation of JNK-mediated apoptotic pathway in SH-SY5Y dopaminergic cells or primary cultured dopaminergic neurons. Our results suggest that upregulated expression of miR-204-5p leads to the death of dopaminergic cells by targeting DYRK1A-mediated ER stress and apoptotic signaling cascade.

G2019S Variation in LRRK2: An Ideal Model for the Study of Parkinson's Disease?

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and has plagued humans for more than 200 years. The etiology and detailed pathogenesis of PD is unclear, but is currently believed to be the result of the interaction between genetic and environmental factors. Studies have found that PD patients with the LRRK2:G2019S variation have the typical clinical manifestations of PD, which may be familial or sporadic, and have age-dependent pathogenic characteristics. Therefore, the LRRK2:G2019S variation may be an ideal model to study the interaction of multiple factors such as genetic, environmental and natural aging factors in PD in the future. This article reviewed the progress of LRRK2:G2019S studies in PD research in order to provide new research ideas and directions for the pathogenesis and treatment of PD.

Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease.

Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.

N-Terminal Acetylation Affects α-Synuclein Fibril Polymorphism.

Parkinson's disease etiology involves amyloid formation by α-synuclein (αSyn). In vivo, αSyn is constitutively acetylated at the α-amino N-terminus. Here, we find N-terminally acetylated αSyn (Ac-αSyn) aggregates more slowly than non-acetylated αSyn (NH3-αSyn) with significantly reduced sensitivity to thioflavin T (ThT). Fibril differences were characterized by transmission electron microscopy, circular dichroism spectroscopy, and limited proteolysis. Interestingly, the low-ThT Ac-αSyn fibrils seed both acetylated and non-acetylated αSyn and faithfully propagate the low-ThT character through several generations, indicating a stable fibril polymorph. In contrast, the high-ThT NH3-αSyn seeds lose fidelity over subsequent generations. Despite it being outside of the amyloid core, the chemical nature of the N-terminus modulates αSyn aggregation and fibril polymorphism.