UNASSIGNED: Nearly two decades after leucine rich repeat kinase 2 (LRRK2) was discovered as a genetic determinant of Parkinson\'s disease (PD), LRRK2 has emerged a priority therapeutic target in PD and inhibition of its activity is hypothesized to be beneficial.
UNASSIGNED: LRRK2 targeting agents, in particular kinase inhibitors and agents reducing LRRK2 expression show promise in model systems and have progressed to phase I and phase II clinical testing for PD. Several additional targeting strategies for LRRK2 are emerging, based on promoting specific \'healthy\' LRRK2 quaternary structures, heteromeric complexes and conformations.
UNASSIGNED: It can be expected that LRRK2 targeting strategies may proceed to phase III clinical testing for PD in the next five years, allowing the field to discover the real clinical value of LRRK2 targeting strategies.

BACKGROUND: Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America.
OBJECTIVE: This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America.
METHODS: We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran\'s Q and I2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers.
RESULTS: We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text.
CONCLUSIONS: This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson\'s disease is one of the most common neurodegenerative diseases affecting the ageing population, with a prevalence that has doubled over the last 30 years. As the mechanism of the disease is not fully elucidated, the current treatments are unable to effectively prevent neurodegeneration. Studies have found that mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most common cause of familial Parkinson\'s disease (PD). Moreover, aberrant (higher) LRRK2 kinase activity has an influence in idiopathic PD as well. Hence, the aim of this review is to categorize and synthesize current information related to LRRK2-linked PD and present the factors associated with LRRK2 that can be targeted therapeutically. A systematic review was conducted using the databases PubMed, Medline, SCOPUS, SAGE, and Cochrane (January 2016 to July 2021). Search terms included \"Parkinson\'s disease\", \"mechanism\", \"LRRK2\", and synonyms in various combinations. The search yielded a total of 988 abstracts for initial review, 80 of which met the inclusion criteria. Here, we emphasize molecular mechanisms revealed in recent in vivo and in vitro studies. By consolidating the recent updates in the field of LRRK2-linked PD, researchers can further evaluate targets for therapeutic application.

Parkinson\'s disease (PD) is a heterogenous neurodegenerative disorder. Genetic factors play a significant role, especially in early onset and familial cases. Mutations are usually found in the LRRK2 gene, but their importance varies. Some mutations, such as p.Arg1441Cys or other alterations in the 1441 codon, show clear correlation with PD, whereas others are risk factors found also in healthy populations or have neglectable consequences. They also exhibit various prevalence among different populations. The aim of this paper is to sum up the current knowledge regarding the epidemiology and pathogenicity of LRRK2 mutations, other than the well-established p.Gly2019Ser. We performed a review of the literature using PubMed database. 103 publications met our inclusion criteria. p.Arg1441Cys, p.Arg1441Gly, p.Arg1441His, p.Arg1441Ser are the most common pathogenic mutations in European populations, especially Hispanic. p.Asn1437His is pathogenic and occurs mostly in the Scandinavians. p.Asn1437Ser and p.Asn1437Asp have been reported in German and Chinese cohorts respectively. p.Ile2020Thr is a rare pathogenic mutation described only in a Japanese cohort. p.Met1869Thr has only been reported in Caucasians. p.Tyr1699Cys, p.Ile1122Val have only been found in one family each. p.Glu1874Ter has been described in just one patient. We found no references concerning mutation p.Gln416Ter. We also report the first case of a Polish PD family whose members carried p.Asn1437His.

Variants in the leucine-rich repeat kinase 2 gene (LRRK2) are risk factors for Parkinson\'s disease (PD), but their prevalence varies geographically, reflecting the locations of founder events and dispersion of founders\' descendants.
A comprehensive literature review was conducted to identify studies providing prevalence estimates for any of ten variants in LRRK2 (G2019S, R1441C, R1441G, R1441H, I2020T, N1437H, Y1699C, S1761R, G2385R, R1628P) among individuals with PD globally. We calculated crude country-specific variant prevalence estimates and, when possible, adjusted estimates for ethno-racial composition. For clinic-based studies, probands were used over other familial cases, whereas for population-based studies, all PD cases were used.
The analysis included 161 articles from 52 countries yielding 581 prevalence estimates across the ten variants. G2019S was the most common variant, exceeding 1.0% in 26 of 51 countries with estimates. The other variants were far less common. G2385R and R1628P were observed almost exclusively in East Asian countries, where they were found in ∼5-10% of cases. All prevalence estimates adjusted for ethno-racial composition were lower than their unadjusted counterparts, although data permitting this adjustment was only available for six countries.
Except for G2019S, the LRRK2 variants covered in this review were uncommon in most countries studied. However, there were countries with higher prevalence for some variants, reflecting the uneven geographic distribution of LRRK2 variants. The fact that ethno-racial group‒adjusted estimates were lower than crude estimates suggests that estimates derived largely from clinic-based studies may overstate the true prevalence of some LRRK2 variants in PD.

A growing amount of evidence has indicated contributions of variants in causative genes of Parkinson\'s disease (PD) to the development of sleep disturbance in PD and prodromal PD stages. In this article, we aimed to investigate the role of genetics in sleep disorders in PD patients and asymptomatic carriers at prodromal stage of PD. A systematic review and meta-analysis of observational studies was conducted based on the MEDLINE, EMBASE and PsychINFO databases. A pooled effect size was calculated by odds ratio (OR) and standard mean difference (SMD). Forty studies were selected for quantitative analysis, including 17 studies on glucocerebrosidase (GBA), 25 studies on Leucine-rich repeat kinase 2 (LRRK2) and 7 on parkin (PRKN) genes, and 3 studies on alpha-synuclein gene (SNCA) were used for qualitative analysis. Patients with PD carrying GBA variants had a significantly higher risk for rapid-eye-movement behavior disorders (RBD) (OR, 1.82) and higher RBD Screening Questionnaire scores (SMD, 0.33). Asymptomatic carriers of GBA variants had higher severity of RBD during follow-up. Patients with PD carrying the LRRK2 G2019S variant had lower risk and severity of RBD compared with those without LRRK2 G2019S. Variants of GBA, LRRK2 and PRKN did not increase or decrease the risk and severity of excessive daytime sleepiness and restless legs syndrome in PD. Our findings suggest that the genetic heterogeneity plays a role in the development of sleep disorders, mainly RBD, in PD and the prodromal stage of PD.

The relationship between Parkinson\'s disease (PD) and cancer has been debated. Gender and genetic influences on cancer development in PD is unclear.
Using QUOROM guidelines, we conducted a systematic review and meta-analysis on potential clinical and genetic factors influencing the PD and subsequent cancer relationship. English articles published in PubMed, Web of Science, and SCOPUS from 2010 to 30 August 2020 were considered for suitability.
Of 46 studies identified, fourteen satisfied the inclusion criteria and were further analysed. Unadjusted risk ratios (RR) and 95% confidence intervals were computed to determine the PD and cancer relationship. PD patients have decreased subsequent cancer risks (RR = 0.87, 95% CI = 0.81-0.93), reduced risks of colon, rectal, and colorectal cancer (RR = 0.77, 95% CI = 0.63-0.94), lung cancer (RR = 0.62, 95% CI = 0.48-0.80), and increased brain cancer (R = 1.48, 95% CI = 1.02-2.13) and melanoma risk (R = 1.76, 95% CI = 1.23-2.50). Compared to idiopathic PD, LRRK2-G2019S carriers had increased general cancer risks (RR = 1.26, 95% CI = 1.09-1.46), particularly brain (RR = 2.41, 95% CI = 1.06-5.50), breast (RR = 2.57, 95% CI = 1.19-5.58), colon (RR = 1.83, 95% CI = 1.13-2.99), and haematological cancers (RR = 2.05, 95% CI = 1.07-3.92). Female PD patients have decreased general cancer risks compared to male PD patients in this analysis (RR = 0.83, 95% CI = 0.69-0.98).
PD patients have reduced risks of colon, rectal, colorectal cancer and lung cancers and increased risks of brain cancer and melanoma. LRRK2-G2019S carriers have increased cancer risks, particularly brain, breast, colon and blood cancers. Female gender was associated with reduced risks. The role of ethnicity, comorbidities, and lifestyle habits on PD patients\' subsequent cancer risk should be further investigated.

Genes associated with parkinsonism may also be implicated in carcinogenesis, but their interplay remains unclear. We systematically reviewed studies (PubMed 1967-2019) reporting gene variants associated with both parkinsonism and cancer. Somatic variants were examined in cancer samples, whereas germline variants were examined in cancer patients with both symptomatic and asymptomatic (carriers) genetic parkinsonisms. Pooled proportions were calculated with random-effects meta-analyses. Out of 9,967 eligible articles, 60 were included. Of the 28 genetic variants associated with parkinsonism, six were also associated with cancer. In cancer samples, SNCA was predominantly associated with gastrointestinal cancers, UCHL1 with breast cancer, and PRKN with head-and-neck cancers. In asymptomatic carriers, LRRK2 was predominantly associated with gastrointestinal and prostate cancers, PRKN with prostate and genitourinary tract cancers, GBA with sarcoma, and 22q11.2 deletion with leukemia. In symptomatic genetic parkinsonism, LRRK2 was associated with nonmelanoma skin cancers and breast cancers, and PRKN with head-and-neck cancers. Cancer was more often manifested in genetic parkinsonisms compared to asymptomatic carriers. These results suggest that intraindividual genetic contributions may modify the co-occurrence of cancer and neurodegeneration.

Introduction: Disease-modifying treatment for Parkinson\'s disease (PD) to halt or revert the disease progression remains an unmet medical need. LRRK2 kinase activity is abnormally elevated in PD patients carrying LRRK2 mutations, with G2019S as the most frequent one. Small molecules to inhibit LRRK2 kinase activity might provide a potential disease-modifying strategy for PD.Areas covered: This review provides an update of small molecule LRRK2 inhibitors in patents published from January 2014 to October 2019. The molecules are classified by their structural scaffolds.Expert opinion: Despite the tremendous efforts to push small molecule LRRK2 inhibitors toward clinical trials, the overall progress is somewhat disappointing due to the challenges in compound optimization and the putative concern of target-related adverse effects. It is challenging to optimize multiple parameters including kinase selectivity, CNS penetration, and unbound fraction in brain simultaneously. In addition, the on-target effect of morphologic changes observed in lung/kidney in pre-clinical studies for several frontrunner ATP-competitive inhibitors prevented their further development. With this regard, non-ATP-competitive inhibitors may provide a different safety profile for development. DNL201 and DNL151 have entered early clinical trials to evaluate tolerability and target engagement biomarkers. This will pave the way for the development for future LRRK2 inhibitors.

Several studies have reported an increased prevalence of Parkinson disease (PD) amongst patients with inflammatory bowel disease (IBD) with conflicting results. We aimed to evaluate the risk of PD in the IBD population by conducting a meta-analysis (MA).
A systematic review with MA of the existing literature was conducted. The main outcome of interest was the incidence of developing PD in patients previously diagnosed with IBD.
Four studies were included in this MA. The overall risk of PD in IBD was significantly higher than controls (RR 1.41, 95% c.i. 1.19-1.66). Crohn\'s disease had a 28% increased risk of PD and ulcerative colitis had a 30% increased risk of PD compared to controls (CD: RR 1.28, 95% c.i. 1.08-1.52, UC: RR 1.30, 95% c.i. 1.15-1.47).
The MA detected an increased risk of PD in the IBD population and CD/UC subgroup. These results merit further clinical validation in future studies.