BACKGROUND: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson\'s disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2.
OBJECTIVE: Our goal was to investigate the effects of genetic variants on risk and time to LID.
METHODS: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID.
RESULTS: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (ORfourth_quartile = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HRthird_quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HRfourth_quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147).
CONCLUSIONS: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

UNASSIGNED: Among LRRK2-associated parkinsonism cases with nigral degeneration, over two-thirds demonstrate evidence of pathologic alpha-synuclein, but many do not. Understanding the clinical phenotype and underlying biology in such individuals is critical for therapeutic development. Our objective was to compare clinical and biomarker features, and rate of progression over 4 years follow-up, among LRRK2-associated parkinsonism cases with and without in vivo evidence of alpha-synuclein aggregates.
UNASSIGNED: Data were from the Parkinson\'s Progression Markers Initiative, a multicenter prospective cohort study. The sample included individuals diagnosed with Parkinson disease with pathogenic variants in LRRK2. Presence of CSF alpha-synuclein aggregation was assessed with seed amplification assay. A range of clinician- and patient- reported outcome assessments were administered. Biomarkers included dopamine transporter SPECT scan, CSF amyloid-beta1-42, total tau, phospho-tau181, urine bis(monoacylglycerol)phosphate levels, and serum neurofilament light chain. Linear mixed effects models examined differences in trajectory in CSF negative and positive groups.
UNASSIGNED: 148 LRRK2-parkinsonism cases (86% with G2019S variant), 46 negative and 102 positive for CSF alpha-synuclein seed amplification assay were included. At baseline, the negative group were older than the positive group (median [interquartile range] 69.1 [65.2-72.3] vs 61.5 [55.6-66.9] years, p<0.001) and a greater proportion were female (28 (61%) vs 43 (42%), p=0.035). Despite being older, the negative group had similar duration since diagnosis, and similar motor rating scale (16 [11-23] vs 16 [10-22], p=0.480) though lower levodopa equivalents. Only 13 (29%) of the negative group were hyposmic, compared to 75 (77%) of the positive group. Lowest putamen dopamine transporter binding expected for age and sex was greater in the negative vs positive groups (0.36 [0.29-0.45] vs 0.26 [0.22-0.37], p<0.001). Serum neurofilament light chain was higher in the negative group compared to the positive group (17.10 [13.60-22.10] vs 10.50 [8.43-14.70]; age-adjusted p-value=0.013). In terms of longitudinal change, the negative group remained stable in functional rating scale score in contrast to the positive group who had a significant increase (worsening) of 0.729 per year (p=0.037), but no other differences in trajectory were found.
UNASSIGNED: Among individuals diagnosed with Parkinson disease with pathogenic variants in the LRRK2 gene, we found clinical and biomarker differences in cases without versus with in vivo evidence of CSF alpha-synuclein aggregates. LRRK2 parkinsonism cases without evidence of alpha-synuclein aggregates as a group exhibit less severe motor manifestations and decline may have more significant cognitive dysfunction. The underlying biology in LRRK2-parkinsonism cases without evidence of alpha-synuclein aggregates requires further investigation.

BACKGROUND: Up to 10 % of Parkinson\'s disease (PD) populations carry a genetic risk variant, which may not only increase one\'s chance of developing PD but also affect disease presentation and progression. We hypothesize motor impairment in genetic carriers of PD correlate to different patterns of microstructural changes over time.
METHODS: Data were accessed from the Parkinson\'s Progression Markers Initiative (PPMI) project. Connectometry analyses were performed for GBA1+ PD, LRRK2+ PD, and sporadic PD correlating white matter structural changes, as measured by quantitative anisotropy (QA), with motor impairment, as measured by MDS-UPDRS III.
RESULTS: There was a negative correlation between QA and MDS-UPDRS III in all 3 cohorts at 48 months. In GBA1+ PD (n = 12), the white matter tracts identified were cortical and subcortical, while in the LRRK2+ PD (n = 18) and sporadic PD (n = 45) cohorts white tracts identified were primarily subcortical and within the brainstem.
CONCLUSIONS: Our findings highlight the association between motor symptom progrerssion and structural connectivity in individuals with GBA1+ PD, LRRK2+ PD, and sporadic PD. Due to the small sample size, larger studies are needed in the future to confirm the findings.

Leucine-rich repeat kinase 2 (LRRK2) c.6055G>A (p.G2019S) is a frequent cause of Parkinson\'s disease (PD), accounting for >30% of Tunisian Arab-Berber patients. LRRK2 is widely expressed in the immune system and its kinase activity confers a survival advantage against infection in animal models. Here, we assess haplotype variability in cis and in trans of the LRRK2 c.6055G>A mutation, define the age of the pathogenic allele, explore its relationship to the age of disease onset (AOO), and provide evidence for its positive selection.

Leucine-rich repeat kinase-2 (LRRK2), a gene mutated in familial and sporadic Parkinson\'s disease (PD), controls multiple cellular processes important for GLIA physiology. Interestingly, emerging studies report that LRRK2 is highly expressed in oligodendrocyte precursor cells (OPCs) compared to the pathophysiology of other brain cells and oligodendrocytes (OLs) in PD. Altogether, these observations suggest crucial function(s) of LRRK2 in OPCs/Ols, which would be interesting to explore. In this study, we investigated the role of LRRK2 in OLs. We showed that LRRK2 knock-out (KO) OPC cultures displayed defects in the transition of OPCs into OLs, suggesting a role of LRRK2 in OL differentiation. Consistently, we found an alteration of myelin basic protein (MBP) striosomes in LRRK2 KO mouse brains and reduced levels of oligodendrocyte transcription factor 2 (Olig2) and Mbp in olig2:EGFP and mbp:RFP transgenic zebrafish embryos injected with lrrk2 morpholino (MO). Moreover, lrrk2 knock-down zebrafish exhibited a lower amount of nerve growth factor (Ngf) compared to control embryos, which represents a potent regulator of oligodendrogenesis and myelination. Overall, our findings indicate that LRRK2 controls OL differentiation, affecting the number of mature OLs.

Pathological mutations in the LRRK2 gene are the major genetic cause of Parkinson\'s disease (PD). Although several animal models with either LRRK2 down- or over-expression have been developed, the physiological function of LRRK2 remains elusive. LRRK2 is constitutively expressed in various tissues including neurons and glial cells, but importantly, it is expressed at low levels in dopaminergic neurons, further contributing to the cryptic function of LRRK2. Significant levels of LRRK2 protein and mRNA have been detected in peripheral blood mononuclear cells, lymph nodes, the spleen, and primary microglia, strongly suggesting the contribution of inflammatory cells to neuronal degeneration. In this research article, using Drosophila LRRK2 models, we were able to demonstrate a significant contribution of glial cells to the LRRK2 pathological phenotype. Furthermore, in Drosophila, neurodegeneration is associated with a significant and important increase in specific inflammatory peptides. Finally, levetiracetam, a compound widely used in human therapy to treat epilepsy, was able to rescue both neuronal degeneration and neuroinflammation.

Targeted delivery of α-synuclein using AAV vectors has over the two decades since its introduction developed into a versatile tool for modeling different aspects of synucleinopathy, mimicking those seen in Parkinson\'s disease and related Lewy body disorders. The viral vector approach to disease modeling is attractive in that the expression of α-synuclein, wild-type or mutated, can be confined to defined anatomical structures and targeted to selected cell populations using either cell-type specific promoter constructs or different natural or engineered AAV serotypes. AAV-α-synuclein was initially used to model progressive α-synuclein pathology in nigral dopamine neurons, and, like the standard 6-OHDA model, it has most commonly been applied unilaterally, using the non-injected side as a reference and control. In recent years, however, the AAV-α-synuclein model has become more widely used to induce Parkinson-like synuclein pathology in other relevant neuronal systems, such as the brainstem noradrenergic and serotonergic neurons, the vagal motor neurons, as well as in oligodendrocytes, the prime target relevant to the pathology seen in multiple system atrophy. The purpose of this review is to give an overview of the progress made in the use of the AAV-α-synuclein model over the last two decades and summarize the state-of-the art in the use of the AAV-α-synuclein model for disease modeling in rats and mice.
Misfolding of the neuronal protein α-synuclein is central to the cellular processes that underlie the development of Parkinson’s disease and related disorders, such as dementia with Lewy bodies and multiple system atrophy. Targeted delivery of α-synuclein using adeno-associated virus, AAV, has become a standard tool to model the disease process in animals. This AAV-α-synuclein model of Parkinson’s disease was introduced two decades ago and over the ensuing decades it has become a widely used standard tool for experimental studies in animals. The usefulness of the AAV-α-synuclein model is largely due to its flexibility and versatility as an experimental tool. In this review the authors summarize the state-of-the art in this field and review the range of applications that has been developed using AAV-α-synuclein alone, in single hit models, or in combinations with other interacting risk factors, in double hit models.

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.

Leucine-rich repeat kinase 2 (LRRK2) is the most common gene responsible for familial Parkinson\'s disease (PD). The gene product of LRRK2 contains multiple protein domains, including armadillo repeat, ankyrin repeat, leucine-rich repeat (LRR), Ras-of-complex (ROC), C-terminal of ROC (COR), kinase, and WD40 domains. In this study, we performed genetic screening of LRRK2 in our PD cohort, detecting sixteen LRRK2 rare variants. Among them, we selected seven variants that are likely to be familial and characterized them in terms of LRRK2 protein function, along with clinical information and one pathological analysis. The seven variants were S1120P and N1221K in the LRR domain; I1339M, S1403R, and V1447M in the ROC domain; and I1658F and D1873H in the COR domain. The kinase activity of the LRRK2 variants N1221K, S1403R, V1447M, and I1658F toward Rab10, a well-known phosphorylation substrate, was higher than that of wild-type LRRK2. LRRK2 D1873H showed enhanced self-association activity, whereas LRRK2 S1403R and D1873H showed reduced microtubule-binding activity. Pathological analysis of a patient with the LRRK2 V1447M variant was also performed, which revealed Lewy pathology in the brainstem. No functional alterations in terms of kinase activity, self-association activity, and microtubule-binding activity were detected in LRRK2 S1120P and I1339M variants. However, the patient with PD carrying LRRK2 S1120P variant also had a heterozygous Glucosylceramidase beta 1 (GBA1) L444P variant. In conclusion, we characterized seven LRRK2 variants potentially associated with PD. Five of the seven variants in different LRRK2 domains exhibited altered properties in kinase activity, self-association, and microtubule-binding activity, suggesting that each domain variant may contribute to disease progression in different ways.

Leucine rich repeat kinase 2 (LRRK2) is a large multidomain protein containing two catalytic domains, a kinase and a GTPase, as well as protein interactions domains, including a WD40 domain. The association of increased LRRK2 kinase activity with both the familial and sporadic forms of Parkinson\'s disease has led to an intense interest in determining its cellular function. However, small molecule probes that can bind to LRRK2 and report on or affect its cellular activity are needed. Here, we report the identification and characterization of the first high-affinity LRRK2-binding designed ankyrin-repeat protein (DARPin), named E11. Using cryo-EM, we show that DARPin E11 binds to the LRRK2 WD40 domain. LRRK2 bound to DARPin E11 showed improved behavior on cryo-EM grids, resulting in higher resolution LRRK2 structures. DARPin E11 did not affect the catalytic activity of a truncated form of LRRK2 in vitro but decreased the phosphorylation of Rab8A, a LRRK2 substrate, in cells. We also found that DARPin E11 disrupts the formation of microtubule-associated LRRK2 filaments in cells, which are known to require WD40-based dimerization. Thus, DARPin E11 is a new tool to explore the function and dysfunction of LRRK2 and guide the development of LRRK2 kinase inhibitors that target the WD40 domain instead of the kinase.