Risk Factor For Parkinson's Disease Research Articles

Large-scale rare variant burden testing in Parkinson's disease.

Parkinson's disease has a large heritable component and genome-wide association studies have identified over 90 variants with disease-associated common variants, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for Parkinson's disease. To address this gap, we investigated the rare genetic component of Parkinson's disease at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7184 Parkinson's disease cases, 6701 proxy cases and 51 650 healthy controls from the Accelerating Medicines Partnership Parkinson's disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank and Genentech. We performed burden tests meta-analyses on small indels and single nucleotide protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. Two of these genes, GBA1 and LRRK2, have variants that have been previously implicated as risk factors for Parkinson's disease, with some variants in LRRK2 resulting in monogenic forms of the disease. We identify potential novel risk associations for variants in B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 and TREML1 but were unable to replicate the observed associations across independent datasets. Of these, B3GNT3 and TREML1 could provide new evidence for the role of neuroinflammation in Parkinson's disease. To date, this is the largest analysis of rare genetic variants in Parkinson's disease.

Amelioration of Parkinson's disease by pharmacological inhibition and knockdown of redox sensitive TRPC5 channels: Focus on mitochondrial health

AimsTransient receptor potential canonical 5 (TRPC5) channels are redox-sensitive cation-permeable channels involved in temperature and mechanical sensation. Increased expression and over-activation of these channels has been implicated in several central nervous system disorders such as epilepsy, depression, traumatic brain injury, anxiety, Huntington's disease and stroke. TRPC5 channel activation causes increased calcium influx which in turn activates numerous downstream signalling pathways involved in the pathophysiology of neurological disorders. Therefore, we hypothesized that pharmacological blockade and knockdown of TRPC5 channels could attenuate the behavioural deficits and molecular changes seen in CNS disease models such as MPTP/MPP+ induced Parkinson's disease (PD). Materials and methodsIn the present study, PD was induced after bilateral intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the Sprague Dawley rats. Additionally, SH-SY5Y neurons were exposed to 1-methyl-4-phenylpyridinium (MPP+) to further determine the role of TRPC5 channels in PD. Key findingsWe used clemizole hydrochloride, a potent TRPC5 channel blocker, to reverse the behavioural deficits, molecular changes and biochemical parameters in MPTP/MPP+-induced PD. Furthermore, knockdown of TRPC5 expression using siRNA also closely phenocopies these effects. We further observed restoration of tyrosine hydroxylase levels and improved mitochondrial health following clemizole treatment and TRPC5 knockdown. These changes were accompanied by diminished calcium influx, reduced levels of reactive oxygen species and decreased apoptotic signalling in the PD models. SignificanceThese findings collectively suggest that increased expression of TRPC5 channels is a potential risk factor for PD and opens a new therapeutic window for the development of pharmacological agents targeting neurodegeneration and PD.

Genetic analysis of transcription factors in dopaminergic neuronal development in Parkinson's disease.

Genetic variants of dopaminergic transcription factor-encoding genes are suggested to be Parkinson's disease (PD) risk factors; however, no comprehensive analyses of these genes in patients with PD have been undertaken. Therefore, we aimed to genetically analyze 16 dopaminergic transcription factor genes in Chinese patients with PD. Whole-exome sequencing (WES) was performed using a Chinese cohort comprising 1917 unrelated patients with familial or sporadic early-onset PD and 1652 controls. Additionally, whole-genome sequencing (WGS) was performed using another Chinese cohort comprising 1962 unrelated patients with sporadic late-onset PD and 1279 controls. We detected 308 rare and 208 rare protein-altering variants in the WES and WGS cohorts, respectively. Gene-based association analyses of rare variants suggested that MSX1 is enriched in sporadic late-onset PD. However, the significance did not pass the Bonferroni correction. Meanwhile, 72 and 1730 common variants were found in the WES and WGS cohorts, respectively. Unfortunately, single-variant logistic association analyses did not identify significant associations between common variants and PD. Variants of 16 typical dopaminergic transcription factors might not be major genetic risk factors for PD in Chinese patients. However, we highlight the complexity of PD and the need for extensive research elucidating its etiology.

Casein Reactivates Dopaminergic Nerve Injury and Intestinal Inflammation with Disturbing Intestinal Microflora and Fecal Metabolites in a Convalescent Parkinson's Disease Mouse Model

Parkinson's disease (PD) is the fastest-growing neurodegenerative disease, with pathogenic causes elusive and short of effective treatment options. Investigations have found that dairy products positively correlate with the onset of PD, but the mechanisms remain unexplored. As casein is an antigenic component in dairy products, this study assessed if casein could exacerbate PD-related symptoms by stimulating intestinal inflammation and unbalanced intestinal flora and be a risk factor for PD. Using a convalescent PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the results showed casein reduced motor coordination, caused gastrointestinal dysfunction, reduced dopamine content, and induced intestinal inflammation. Meanwhile, casein disturbed gut microbiota homeostasis by increasing the Firmicutes/Bacteroidetes ratio, decreasing α-diversity, and caused abnormal alterations in fecal metabolites. However, these adverse effects of casein attenuated much when it had hydrolyzed by acid or when antibiotics inhibited the intestinal microbiota of the mice. Therefore, our results suggested that casein could reactivate dopaminergic nerve injury and intestinal inflammation and exacerbate intestinal flora disorder and its metabolites in convalescent PD mice. These damaging effects might be related to disordered protein digestion and gut microbiota in these mice. These findings will provide new insights into the impact of milk/dairy products on PD progression and supply information on dietary options for PD patients.

Mutant LRRK2 exacerbates immune response and neurodegeneration in a chronic model of experimental colitis

The link between the gut and the brain in Parkinson’s disease (PD) pathogenesis is currently a subject of intense research. Indeed, gastrointestinal dysfunction is known as an early symptom in PD and inflammatory bowel disease (IBD) has recently been recognised as a risk factor for PD. The leucine-rich repeat kinase 2 (LRRK2) is a PD- and IBD-related protein with highest expression in immune cells. In this study, we provide evidence for a central role of LRRK2 in gut inflammation and PD. The presence of the gain-of-function G2019S mutation significantly increases the disease phenotype and inflammatory response in a mouse model of experimental colitis based on chronic dextran sulphate sodium (DSS) administration. Bone marrow transplantation of wild-type cells into G2019S knock-in mice fully rescued this exacerbated response, proving the key role of mutant LRRK2 in immune cells in this experimental colitis model. Furthermore, partial pharmacological inhibition of LRRK2 kinase activity also reduced the colitis phenotype and inflammation. Moreover, chronic experimental colitis also induced neuroinflammation and infiltration of peripheral immune cells into the brain of G2019S knock-in mice. Finally, combination of experimental colitis with overexpression of α-synuclein in the substantia nigra aggravated motor deficits and dopaminergic neurodegeneration in G2019S knock-in mice. Taken together, our results link LRRK2 with the immune response in colitis and provide evidence that gut inflammation can impact brain homeostasis and contribute to neurodegeneration in PD.

Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson’s iPSC-dopamine neurons

Parkinson's disease (PD) is characterized by a progressive deterioration of motor and cognitive functions. Although death of dopamine neurons is the hallmark pathology of PD, this is a late-stage disease process preceded by neuronal dysfunction. Here we describe early physiological perturbations in patient-derived induced pluripotent stem cell (iPSC)-dopamine neurons carrying the GBA-N370S mutation, a strong genetic risk factor for PD. GBA-N370S iPSC-dopamine neurons show an early and persistent calcium dysregulation notably at the mitochondria, followed by reduced mitochondrial membrane potential and oxygen consumption rate, indicating mitochondrial failure. With increased neuronal maturity, we observed decreased synaptic function in PD iPSC-dopamine neurons, consistent with the requirement for ATP and calcium to support the increase in electrophysiological activity over time. Our work demonstrates that calcium dyshomeostasis and mitochondrial failure impair the higher electrophysiological activity of mature neurons and may underlie the vulnerability of dopamine neurons in PD.

COVID-19 and neurological disorders: what might connect Parkinson's disease to SARS-CoV-2 infection.

SARS-CoV-2 infection leading to Coronavirus disease 19 (COVID-19) rapidly became a worldwide health emergency due to its elevated infecting capacity, morbidity, and mortality. Parkinson’s disease (PD) is the second most common neurodegenerative disorder and, nowadays the relationship between SARS-CoV-2 outbreak and PD reached a great interest. Apparently independent one from the other, both diseases share some pathogenetic and clinical features. The relationship between SARS-CoV-2 infection and PD is complex and it depends on the direction of the association that is which of the two diseases comes first. Some evidence suggests that SARS-CoV-2 infection might be a possible risk factor for PD wherein the exposure to SARS-CoV-2 increase the risk for PD. This perspective comes out from the increasing cases of parkinsonism following COVID-19 and also from the anatomical structures affected in both COVID-19 and early PD such as olfactory bulb and gastrointestinal tract resulting in the same symptoms such as hyposmia and constipation. Furthermore, there are many reported cases of patients who developed hypokinetic extrapyramidal syndrome following SARS-CoV-2 infection although these would resemble a post-encephalitic conditions and there are to date relevant data to support the hypothesis that SARS-CoV-2 infection is a risk factor for the development of PD. Future large, longitudinal and population-based studies are needed to better assess whether the risk of developing PD after COVID-19 exists given the short time span from the starting of pandemic. Indeed, this brief time-window does not allow the precise estimation of the incidence and prevalence of PD after pandemic when compared with pre-pandemic era. If the association between SARS-CoV-2 infection and PD pathogenesis is actually putative, on the other hand, vulnerable PD patients may have a greater risk to develop COVID-19 being also more prone to develop a more aggressive disease course. Furthermore, PD patients with PD showed a worsening of motor and non-motor symptoms during COVID-19 outbreak due to both infection and social restriction. As well, the worries related to the risk of being infected should not be neglected. Here we summarize the current knowledge emerging about the epidemiological, pathogenetic and clinical relationship between SARS-CoV-2 infection and PD.

Association of 99MTC- Hmpao Spect Measured Regional Cerebral Blood Flow And Serum Vitamin D Level With Clinical Staging of Parkinson’s Disease

Background: Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. Diagnosis of PD can be made through Single-photon emission computed tomography (SPECT). Vitamin D deficiency has recently been proposed as a potential risk factor for PD. This study aimed to evaluate the association of 99mTc- HMPAO SPECT image findings and vitamin D status with clinical staging of PD. Methods: This cross-sectional study was conducted in Department of Neurology, Sir Salimullah Medical College Mitford Hospital for a period of 12 months. Total 66 diagnosed PD patients were included after taking informed written consent. Detailed demographic history and neurological examination were done. The severity of PD was assessed using the modified Hoehn and Yahr (H &amp; Y) scale. Serum 25-Hydroxyvitamin D level was measured for each participant. 99mTc- HMPAO SPECT imaging was done at Institute of Nuclear Medicine and Allied Sciences. Results: The mean age of the studied respondents was 71±8.72 (SD) years wherein maximum were male (59.1%) and aged above 70 years. The most common symptoms among the patients were tremor (78.8%) and bradykinesia (75.5%).The mean duration of PD was 5.74±2.22 (SD) years. Majority of the patients were diagnosed to have stage-2 (30.3%) followed by stage-2.5 (24.2%), stage-3 (16.7%), stage-4 (7.6%), stage-1 (4.5%), and stage-5 (3%). As the clinical stage of PD advanced from stages 1-5, the HMPAO uptake reduced significantly in the basal ganglia (p=0.006) .Vitamin-D level decreased significantly as the disease severity progress from stage-1 (27.8 ng/ml) to stage-5 (19.5 ng/ml) (p-value=0.008). Conclusion: Serum Vitamin-D level was inversely associated to severity of PD and decreased regional cerebral blood flow in basal ganglia in advanced stages of PD patients. However, further larger study is recommended. Bangladesh J Medicine 2023; 34(2): 112-120

Identification of candidate Parkinson’s disease predisposition genes in high-risk pedigrees (S42.001)

<h3>Objective:</h3> To identify rare genetic variants associated with increased risk of Parkinson’s disease (PD) in multi-generation, high-risk pedigrees. <h3>Background:</h3> Monogenic forms and genetic risk factors for PD have been identified, but together they explain only a fraction of familial and sporadic PD. High-risk pedigree studies offer a powerful method for identification of genetic variants affecting predisposition to PD. <h3>Design/Methods:</h3> Previously sampled PD-affected relatives belonging to pedigrees exhibiting a statistically significant excess of PD were whole exome sequenced (WES) to identify rare, shared variants as candidate predisposition variants for PD. We identified pedigrees with high-risk of PD using the Utah Population Database (UPDB), a resource linking extensive genealogy information with medical record and other public health data sources. PD cases were identified by PD listed as a cause of death on death certificates. Sequencing results were compared to association results in the PD DNA Variant Browser. <h3>Results:</h3> We identified 2,357 clusters/pedigrees that included from 2 to 43 sampled individuals with PD-related deaths. From this group, we selected 379 high-risk clusters with 2–37 PD cases and significant excess of PD among pedigree members (p&lt;0.05). We then selected 25/379 pedigrees with a significant excess of PD cases and at least one pair of related DNA case samples. WES and bioinformatics analysis of a PD-affected cousin pair from each high-risk pedigree identified 242 rare, shared variants in 221 genes. Of these, 16 genes showed significant association with PD risk in the PD DNA Variant Browser. <h3>Conclusions:</h3> WES in pairs of related sampled PD cases from high-risk pedigrees led to the identification of shared DNA variants in 221 genes, 16 of which were identified in previous studies. Validation studies of some of these candidate PD predisposition variants in these families are currently underway. <b>Disclosure:</b> The institution of an immediate family member of Dr. Moretti has received research support from NIH. The institution of an immediate family member of Dr. Moretti has received research support from VHA. The institution of an immediate family member of Dr. Moretti has received research support from DOD. Ms. Figueroa has nothing to disclose. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for venrock. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leverna. Dr. Pulst has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Leninthal LLC. The institution of Dr. Pulst has received research support from NINDS. Dr. Pulst has received intellectual property interests from a discovery or technology relating to health care. Mr. Dotti has nothing to disclose. Jeff Stevens has nothing to disclose. Dr. Allen-Brady has nothing to disclose. The institution of Lisa A. Cannon-Albright has received research support from huntsman cancer institute.

Metal Exposure and Risk of Parkinson Disease: A Systematic Review and Meta-Analysis.

Metal exposure has been suggested as a possible environmental risk factor for Parkinson disease (PD). We searched the PubMed, EMBASE, and Cochrane databases to systematically review the literature on the relationship between metal exposure and PD risk and to examine the overall quality of each study and the exposure assessment method. A total of 83 case-control studies and 5 cohort studies published duringthe period 1963-July 2021 were included, of which 73 were graded as being of low or moderate overall quality. Investigators in 69 studies adopted self-reported exposure and biomonitoring after disease diagnosis for exposure assessment approaches. The meta-analyses showed that concentrations of copper and iron in serum and concentrations of zinc in either serum or plasma were lower, while concentrations of magnesium in CSF and zinc in hair were higher, among PD cases as compared with controls. Cumulative lead levels in bone were found to be associated with increased risk of PD. We did not find associations between other metals and PD. The current level of evidence for associations between metals and PD risk is limited, as biases from methodological limitations cannot be ruled out. High-quality studies assessing metal levels before disease onset are needed to improve our understanding of the role of metals in the etiology of PD.

Downregulation of striatal CaV1.3 inhibits the escalation of levodopa-induced dyskinesia in male and female parkinsonian rats of advanced age

In the past 25 years, the prevalence of Parkinson's disease (PD) has nearly doubled. Age remains the primary risk factor for PD and as the global aging population increases this trend is predicted to continue. Even when treated with levodopa, the gold standard dopamine (DA) replacement therapy, individuals with PD frequently develop therapeutic side effects. Levodopa-induced dyskinesia (LID), a common side effect of long-term levodopa use, represents a significant unmet clinical need in the treatment of PD. Previously, in young adult (3-month-old) male parkinsonian rats, we demonstrated that the silencing of CaV1.3 (Cacan1d) L-type voltage-gated calcium channels via striatal delivery of rAAV-CaV1.3-shRNA provides uniform protection against the induction of LID, and significant reduction of established severe LID. With the goal of more closely replicating a clinical demographic, the current study examined the effects of CaV1.3-targeted gene therapy on LID escalation in male and female parkinsonian rats of advanced age (18-month-old at study completion). We tested the hypothesis that silencing aberrant CaV1.3 channel activity in the parkinsonian striatum would prevent moderate to severe dyskinesia with levodopa dose escalation. To test this hypothesis, 15-month-old male and female F344 rats were rendered unilaterally parkinsonian and primed with low-dose (3–4 mg/kg) levodopa. Following the establishment of stable, mild dyskinesias, rats received an intrastriatal injection of either the Cacna1d-specific rAAV-CaV1.3-shRNA vector (CAV-shRNA), or the scramble control rAAV-SCR-shRNA vector (SCR-shRNA). Daily (M-Fr) low-dose levodopa was maintained for 4 weeks during the vector transduction and gene silencing window followed by escalation to 6 mg/kg, then to 12 mg/kg levodopa. SCR-shRNA-shRNA rats showed stable LID expression with low-dose levodopa and the predicted escalation of LID severity with increased levodopa doses. Conversely, complex behavioral responses were observed in aged rats receiving CAV-shRNA, with approximately half of the male and female subjects—therapeutic ‘Responders’—demonstrating protection against LID escalation, while the remaining half—therapeutic ‘Non-Responders’—showed LID escalation similar to SCR-shRNA rats. Post-mortem histological analyses revealed individual variability in the detection of Cacna1d regulation in the DA-depleted striatum of aged rats. However, taken together, male and female therapeutic ‘Responder’ rats receiving CAV-shRNA had significantly less striatal Cacna1d in their vector-injected striatum relative to contralateral striatum than those with SCR-shRNA. The current data suggest that mRNA-level silencing of striatal CaV1.3 channels maintains potency in a clinically relevant in vivo scenario by preventing dose-dependent dyskinesia escalation in rats of advanced age. As compared to the uniform response previously reported in young male rats, there was notable variability between individual aged rats, particularly females, in the current study. Future investigations are needed to derive the sex-specific and age-related mechanisms which underlie variable responses to gene therapy and to elucidate factors which determine the therapeutic efficacy of treatment for PD.

Sexual dysfunction precedes motor defects, dopaminergic neuronal degeneration, and impaired dopamine metabolism: Insights from Drosophila model of Parkinson's disease.

Sexual dysfunction (SD) is one of the most common non-motor symptoms of Parkinson's disease (PD) and remains the most neglected, under-reported, and under-recognized aspect of PD. Studies have shown that Dopamine (DA) in the hypothalamus plays a role in regulating sexual behavior. But the detailed mechanism of SD in PD is not known. Drosophila melanogaster shares several genes and signaling pathways with humans which makes it an ideal model for the study of a neurodegenerative disorder such as PD. Courtship behavior of Drosophila is one such behavior that is closely related to human sexual behavior and so plays an important role in understanding sexual behavior in diseased conditions as well. In the present study, a sporadic SD model of PD using Drosophila was developed and SD phenotype was observed based on abnormalities in courtship behavior markers. The Drosophila SD model was developed in such a way that at the window of neurotoxin paraquat (PQ) treatment [PQ is considered a crucial risk factor for PD due to its structural similarity with 1-methyl-4-phenyl pyridinium (MPP+), the active form of PD-inducing agent, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)], it does not exhibit mobility defects but shows SD. The whole brain tyrosine hydroxylase immunostaining showed no observable dopaminergic (DAergic) degeneration (number of DA neurons and fluorescence intensity of fluorescently labeled secondary antibodies that target anti-TH primary antibody) of the SD model. Similarly, there was no significant depletion of brain DA and its metabolite levels (HVA and DOPAC) as determined using HPLC-ECD (High-Performance Liquid Chromatography using Electrochemical Detector). The present study illustrates that the traits associated with courtship and sexual activity provide sensitive markers at the earlier stage of PD onset. This PQ-induced SD fly model throws an opportunity to decipher the molecular basis of SD under PD conditions and to screen nutraceuticals/potential therapeutic molecules to rescue SD phenotype and further to DAergic neuroprotection.

Two Different PRKN Compound Heterozygous Variants Combinations in the Same Family.

Two Different PRKN Compound Heterozygous Variants Combinations in the Same Family.

Infectious Microorganisms Seen as Etiologic Agents in Parkinson’s Disease

Infections represent a possible risk factor for parkinsonism and Parkinson's disease (PD) based on information from epidemiology and fundamental science. The risk is unclear for the majority of agents. Moreover, the latency between infection and PD seems to be very varied and often lengthy. In this review, the evidence supporting the potential involvement of infectious microorganisms in the development of Parkinson's disease is examined. Consequently, it is crucial to determine the cause and give additional treatment accordingly. Infection is an intriguing suggestion regarding the cause of Parkinson's disease. These findings demonstrate that persistent infection with viral and bacterial microorganisms might be a cause of Parkinson's disease. As an initiating factor, infection may generate a spectrum of gut microbiota dysbiosis, engagement of glial tissues, neuroinflammation, and alpha-synuclein accumulation, all of which may trigger and worsen the onset in Parkinson's disease also contribute to its progression. Still uncertain is the primary etiology of PD with infection. The possible pathophysiology of PD infection remains a matter of debate. Furthermore, additional study is required to determine if PD patients develop the disease due to infectious microorganisms or solely since they are more sensitive to infectious causes.

Structural Variants of Midnolin, a Genetic Risk Factor for Parkinson's Disease, in a Yamagata Cohort.

Parkinson's disease (PD) is a common neurodegenerative disease. We previously identified Midnolin (MIDN) to be a genetic risk factor for PD in both Yamagata (Japan) and British populations. However, the scale of our previous study was not sufficient to identify MIDN structural variants in the ascertained control of Yamagata Prefecture. We, therefore, reanalyzed MIDN variants in 3021 individuals from Yamagata Prefecture to compare with that in our previous British cohort study. MIDN copy number loss was only found in two cases (0.0662%), which was a lower frequency than that (1.64%) of the previously studied British cohort. Between the Yamagata and British groups, there was significant difference for rs3746106, located in the 5'-UTR of MIDN mRNA (p = 0.0003344, odds ratio 1.143), and for rs3746107, which corresponds to Ala34 (p < 2.2 × 10-16, odds ratio 5.89401). This study indicates that MIDN loss is relatively rare in the general Japanese population. Considering our previous studies that the frequency of MIDN loss is high among patients with PD (10.5 and 6.55% in Yamagata and Britain, respectively), the MIDN variants are much higher genetic risk factors for PD in a Japanese population than in a British population.

Incidence of Parkinson's disease and modifiable risk factors in Korean population: A longitudinal follow-up study of a nationwide cohort.

We aimed to investigate the incidence of Parkinson's disease (PD) by age and year for each sex as well as the modifiable risk factors for PD. Using data from the Korean National Health Insurance Service, 938,635 PD and dementia-free participants aged ≥40 years who underwent general health examinations were followed to December 2019. We analyzed the PD incidence rates according to age, year and sex. To investigate the modifiable risk factors for PD, we used the Cox regression model. Additionally, we calculated the population-attributable fraction to measure the impact of the risk factors on PD. During follow-up, 9,924 of the 938,635 (1.1%) participants developed PD. The incidence of PD increased continuously from 2007 to 2018, reaching 1.34 per 1,000 person-years in 2018. The incidence of PD also increases with age, up to 80 y. Presence of hypertension (SHR = 1.09, 95% CI 1.05 to 1.14), diabetes (SHR = 1.24, 95% CI 1.17 to 1.31), dyslipidemia (SHR = 1.12, 95% CI 1.07 to 1.18), ischemic stroke (SHR = 1.26, 95% CI 1.17 to 1.36), hemorrhagic stroke (SHR = 1.26, 95% CI 1.08 to 1.47), ischemic heart disease (SHR = 1.09, 95% CI 1.02 to 1.17), depression (SHR = 1.61, 95% CI 1.53 to 1.69), osteoporosis (SHR = 1.24, 95% CI 1.18 to 1.30), and obesity (SHR = 1.06, 95% CI 1.01 to 1.10) were independently associated with a higher risk for PD. Our results highlight the effect of modifiable risk factors for PD in the Korean population, which will help establish health care policies to prevent the development of PD.

The Development and Design Strategy of Leucine-Rich Repeat Kinase 2 Inhibitors: Promising Therapeutic Agents for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting millions of people worldwide. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common genetic risk factor for PD. Elevated LRRK2 kinase activity is found in idiopathic and familial PD cases. LRRK2 mutations are involved in multiple PD pathogeneses, including dysregulation of mitochondrial homeostasis, ciliogenesis, etc. Here, we provide a comprehensive overview of the biological function, structure, and mutations of LRRK2. We also examine recent advances and challenges in developing LRRK2 inhibitors and address prospective protein-based targeting strategies. The binding mechanisms, structure-activity relationships, and pharmacokinetic features of inhibitors are emphasized to provide a comprehensive compendium on the rational design of LRRK2 inhibitors. We hope that this publication can serve as a guide for designing novel LRRK2 inhibitors based on the summarized facts and perspectives.

Genome-Wide Analysis of Structural Variants in Parkinson Disease.

Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD. We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data. We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2kb intronic deletion within the gene LRRN4. We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012-1022.

DNA Methylation of α-Synuclein Intron 1 Is Significantly Decreased in the Frontal Cortex of Parkinson's Individuals with GBA1 Mutations.

Parkinson's disease (PD) is a common movement disorder, estimated to affect 4% of individuals by the age of 80. Mutations in the glucocerebrosidase 1 (GBA1) gene represent the most common genetic risk factor for PD, with at least 7-10% of non-Ashkenazi PD individuals carrying a GBA1 mutation (PD-GBA1). Although similar to idiopathic PD, the clinical presentation of PD-GBA1 includes a slightly younger age of onset, a higher incidence of neuropsychiatric symptoms, and a tendency to earlier, more prevalent and more significant cognitive impairment. The pathophysiological mechanisms underlying PD-GBA1 are incompletely understood, but, as in idiopathic PD, α-synuclein accumulation is thought to play a key role. It has been hypothesized that this overexpression of α-synuclein is caused by epigenetic modifications. In this paper, we analyze DNA methylation levels at 17 CpG sites located within intron 1 and the promoter of the α-synuclein (SNCA) gene in three different brain regions (frontal cortex, putamen and substantia nigra) in idiopathic PD, PD-GBA1 and elderly non-PD controls. In all three brain regions we find a tendency towards a decrease in DNA methylation within an eight CpG region of intron 1 in both idiopathic PD and PD-GBA1. The trend towards a reduction in DNA methylation was more pronounced in PD-GBA1, with a significant decrease in the frontal cortex. This suggests that PD-GBA1 and idiopathic PD have distinct epigenetic profiles, and highlights the importance of separating idiopathic PD and PD-GBA1 cases. This work also provides initial evidence that different genetic subtypes might exist within PD, each characterized by its own pathological mechanism. This may have important implications for how PD is diagnosed and treated.

Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neurons in vitro and in vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice; GdnfcHyper ). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and nonmotor symptoms in the proteasome inhibitor lactacystin (LC) model of PD. Our results showed that upregulation of endogenous GDNF in the adult striatum is not protective in LC-induced PD model in mice. Since age is the largest risk factor for PD, we also analyzed the effect of deletion of endogenous GDNF in aged Gdnf conditional knock-out mice. We found that GDNF deletion does not increase susceptibility to LC-induced damage. We conclude that endogenous GDNF does not impact the outcome in the LC-induced proteasome inhibition mouse model of Parkinson's disease.