Unravelling LRRK2 Pathways in Parkinson's Disease: Mechanisms and Intricacies

Familial Aggregation of Panic Disturbances in Parkinson's Disease

Rare and common LRRK2 exonic variants in Parkinson's disease

Parkinson disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and non-motor symptoms. Idiopathic PD is the most common cause of Parkinsonism (primary Parkinsonism) while, certain medication and different groups of neurological disorder may be causes of secondary Parkinsonism. The presence of intraneuronal proteinaceous cytoplasmic inclusions “Lewy Bodies” and the loss of the nigrostriatal dopaminergic neurons are the main neuropathological hallmarks of PD. However, the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, neuroinflammation, apoptosis and excitotoxicity play vital roles in the pathogenesis and progress of the disease. Experimental models of PD can be induced by several neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone and paraquat which produce neuropathological and neurochemical changes that are identical to those seen in PD. The primary drug for PD treatment is L-dopa; however, drug-induced dyskinesia and motor complications restricted its use as long term treatment. Dopamine agonists are alternative options for initial treatment of PD and have been reported to retard the onset of motor complications. Combination of L-dopa with other medications, such ascatechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors has the ability to alleviate L-dopa-induced motor complications. Anticholinergic drugs can be used to control the symptoms of PD but their cognitive and autonomic side effects make them unsuitable for the elderly.

Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.

Genetic screening for LRRK2 gene G2019S mutation in Parkinson's disease patients from Southern Italy

SummaryBackgroundMutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2?MethodsResearchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD.FindingsSix mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD.InterpretationMutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients.FundingUK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

Surprising behavioral and neurochemical enhancements in mice with combined mutations linked to Parkinson's disease

The purpose of this review is to outline the impact of the COVID-19 pandemic on movement disorder holistic care, particularly in the care of people with Parkinson disease (PWP). As the pandemic unfolds, a flurry of literature was published regarding the impact of COVID-19 on people with Parkinson disease including the direct impact of infection, availability of ambulatory care, loss of community-based team care, and acceptability of telemedicine. COVID-19 has impacted the care of PWP in numerous ways. Recognizing infection in PWP poses challenges. Specific long-term complications, including emerging reports of long COVID syndrome is a growing concern. Caregivers and PWP have also been impacted by COVID-19 social isolation restrictions, with radical changes to the structure of social networks and support systems globally. In a matter of weeks, the global community saw an incredible uptake in telemedicine, which brought benefits and pitfalls. As PWP adapted to virtual platforms and the changing architecture of care delivery, the pandemic amplified many preexisting inequities amongst populations and countries, exposing a new 'digital divide'.

Linkage analysis in familial Parkinson's disease (PD) identified a locus in 2q36-37 (PARK11). Sequencing of GIGYF2 identified several variants only present amongst PD individuals. We analyzed the presence of disease-associated GIGYF2 variants in familial and sporadic PD from Spanish origin by sequencing of 147 PD individuals. The entire GIGYF2 coding sequence was analyzed in 122 familial PD individuals and exons 2, 4, 8-11, 14 and 25-26 were sequenced in 25 sporadic PD to identify disease-associated variants. We found no variants associated with PD and failed to identify any of previously PD-associated GIGYF2 variants in our sample. We identified four novel missense changes in GIGYF2. p.Met48Ile was found in a PD individual who also was a carrier of two PARKIN mutations. p.Q1244_Q1247del variant was present only in one PD individual but not found in 70 controls. However, its location in the highly polymorphic GIGYF2 glutamine/proline-rich region does not support a role in PD. Two variants (p.P1238insAGC and p.Q1249del) were present both in PD subjects and in controls. Additionally, the p.L1230_Q1237del variant, which was previously considered as a PD-associated change, was found in one control. Our findings suggest that GIGYF2 mutations are not a frequent cause of PD in the Spanish population, since we found no clearly segregating variants. We propose further analyses in PD subjects from different populations to define the role of GIGYF2. A clear pathogenic mutation in other gene at 2q36-37 in the PARK11-linked PD families would definitively disprove GIGYF2 as the responsible gene.

Introduction and Purpose. Parkinson’s Disease (PD) is a chronic neurodegenerative disorder caused by dopamine deficiency due to neuronal degeneration, leading to motor and non-motor symptoms. Gastrointestinal symptoms are common and often precede motor symptoms. There is increasing evidence that imbalanced gut microbiota may influence the gut-brain axis and contribute to motor and non-motor PD symptoms. Fecal microbiota transplantation (FMT) may have the potential to restore gut flora and improve PD symptoms. The study aims to explore the current knowledge on the impact of FMT on PD symptoms, acknowledging existing reviews and highlighting new studies not yet reviewed. Understanding the underlying causes of PD could lead to better treatment, diagnostics, and prevention.State of knowledge. PD patients suffer from specific gut dysbiosis which leads to imbalance in the produced pro- and anti-inflammatory substances in the intestinal lumen resulting in aggreviation of α-synuclein in gut nervous cells which may hypothetically transfer via vagal nerve to CNS causing PD. In animal research FMT showed promising results in alleviating PD symptoms. Case reports showed reduction of both motor and non-motor dysfunctions, especially in constipation. DuPont et al. showed improvements in constipation, motor deficits, overall Parkinson’s symptoms, and some non-motor disorders. Cheng et al. showed improvements in MDS-UPDRS, scores of GI tract symptoms scales, PD-related autonomic symptoms and the stool frequency. Bruggeman et al. showed better MDS-UPDRS part 3 scores and better colon transit, but no significant differencies in any other tested domains. Conclusions. As there is yet no standarized protocol for FMT, all of the past research used different techniques and showed slightly different outcomes, but all have shown that FMT have some positive effects on PD symptoms.

Background: Parkinson’s disease (PD), although widely heterogeneous and manifesting with numerous motor and non-motor symptoms, presents clinically as a single entity worldwide. Its genetic causes are also heterogeneous and include highly penetrant variants in a single gene representing rare monogenic forms, and rare or common variants conferring a relative disease risk representing more frequent multigenic forms. Most of these variants have been discovered in patients of European ancestry. Since the genetic basis of PD can vary significantly between populations due to differences in allele frequencies, little is known about the genetics of PD in other populations, particularly from Africa. Morocco, located in a region of North Africa, constitutes a subcontinent known for a weak external genetic influence and for a local genetic continuity for millennia, which makes it a region of interest to study the genetic causes of PD. Summary: This review aimed to summarize published research data on the genetic profile of PD patients from the Moroccan population to describe its genetic architecture. Unlike in Western countries, PD in Morocco is predominantly a Mendelian disease reaching up to 50%, due to the high prevalence of the LRRK2 G2019S dominant variant and to relatively less frequent PRKN and PINK1 recessive variants due to the high rate of consanguinity. Additionally, rare high-risk variants in LRRK2, VPS13C, MAPT, and POLG, in oligo- or polygenic ways, may contribute to increasing the genetic risk of the disease. Key Messages: We, therefore, show that the genetic architecture of PD in Morocco, a country in the subcontinent of North Africa, was different from that of sub-Saharan Africa and the rest of the world. This will help improve diagnostic accuracy, subdivide the clinical variability of the disease into groups of common genetic and biological causes for a better therapeutic management strategy, and test molecules from ongoing clinical trials.

Parkinson's disease (PD) is a systemic neurodegenerative disorder that is characterized by motor and non-motor symptoms. Although aging is the primary risk factor, environmental and genetic factors also contribute to risk, and identifying genetic risks may aid in preventive strategies. The present perspective outlines the two main genetic research strategies: research into familial PD using known causative gene screening and next-generation sequencing, and the analysis of sporadic PD using genome-wide association studies (GWAS). Recent advances in next-generation sequencing have improved gene screening, allowing researchers to quickly and inexpensively identify novel rare variants. However, challenges remain, such as accurately analyzing repetitive sequences and structural variants. The role of neurologists in gathering clinical and genomic data ─ especially from familial cases ─ is crucial. International collaborations, such as the Global Parkinson's Genetic Program, address issues such as population diversity and missing heritability in GWAS. Contributions from Juntendo University include the discovery of PD-related genes and the implementation of validation studies in Japanese populations. We also aim to develop molecular targeted therapies using induced pluripotent stem cells. To elucidate the unknown causes of PD and advance treatment approaches, it is important to continuously conduct genetic research.

Translation Initiator EIF4G1 Mutations in Familial Parkinson Disease

SummaryBackgroundParkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease.MethodsWe did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case–control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities.FindingsBetween June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38–96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15–87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31–81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71.InterpretationRAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling.FundingNational Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Systemic Exosomal Delivery of shRNA Minicircles Prevents Parkinsonian Pathology.