Perspective on the current state of the LRRK2 field

Taymans, Jean-Marc; Fell, Matthew; Greenamyre, Tim; Hirst, Warren D.; Mamais, Adamantios; Padmanabhan, Shalini; Peter, Inga; Rideout, Hardy J.; Thaler, Avner

doi:10.1038/s41531-023-00544-7

Cited by 50 publications

(18 citation statements)

References 127 publications

(156 reference statements)

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“…Applying our approach, we identified novel candidate genes implicated in inflammation and autophagy, which may play a role in the pathogenesis of IBD-PD comorbidity. However, it is important to consider the potential impact of incomplete penetrance, a common feature of many genetic diseases, including PD [ 94 ], on the manifestation of the disease in variant carriers. A thorough evaluation of the penetrance of our detected putative disease-causing variants can be more effectively performed in large case–control studies [ 95 ].…”

Section: Discussionmentioning

confidence: 99%

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Kars,

Wu,

Stenson

et al. 2024

Genome Med

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Background Inflammatory bowel disease (IBD) and Parkinson’s disease (PD) are chronic disorders that have been suggested to share common pathophysiological processes. LRRK2 has been implicated as playing a role in both diseases. Exploring the genetic basis of the IBD-PD comorbidity through studying high-impact rare genetic variants can facilitate the identification of the novel shared genetic factors underlying this comorbidity. Methods We analyzed whole exomes from the BioMe BioBank and UK Biobank, and whole genomes from a cohort of 67 European patients diagnosed with both IBD and PD to examine the effects of LRRK2 missense variants on IBD, PD and their co-occurrence (IBD-PD). We performed optimized sequence kernel association test (SKAT-O) and network-based heterogeneity clustering (NHC) analyses using high-impact rare variants in the IBD-PD cohort to identify novel candidate genes, which we further prioritized by biological relatedness approaches. We conducted phenome-wide association studies (PheWAS) employing BioMe BioBank and UK Biobank whole exomes to estimate the genetic relevance of the 14 prioritized genes to IBD-PD. Results The analysis of LRRK2 missense variants revealed significant associations of the G2019S and N2081D variants with IBD-PD in addition to several other variants as potential contributors to increased or decreased IBD-PD risk. SKAT-O identified two significant genes, LRRK2 and IL10RA, and NHC identified 6 significant gene clusters that are biologically relevant to IBD-PD. We observed prominent overlaps between the enriched pathways in the known IBD, PD, and candidate IBD-PD gene sets. Additionally, we detected significantly enriched pathways unique to the IBD-PD, including MAPK signaling, LPS/IL-1 mediated inhibition of RXR function, and NAD signaling. Fourteen final candidate IBD-PD genes were prioritized by biological relatedness methods. The biological importance scores estimated by protein–protein interaction networks and pathway and ontology enrichment analyses indicated the involvement of genes related to immunity, inflammation, and autophagy in IBD-PD. Additionally, PheWAS provided support for the associations of candidate genes with IBD and PD. Conclusions Our study confirms and uncovers new LRRK2 associations in IBD-PD. The identification of novel inflammation and autophagy-related genes supports and expands previous findings related to IBD-PD pathogenesis, and underscores the significance of therapeutic interventions for reducing systemic inflammation.

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Section: Discussionmentioning

confidence: 99%

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Kars,

Wu,

Stenson

et al. 2024

Genome Med

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“…Moreover, lower penetrance rates in genetically at-risk individuals such as carriers of pathogenic LRRK2 or GBA variants complicate trial design and statistical power in the absence of established validated biomarkers for these targets that go beyond alpha synuclein. However, low-risk prevention interventions in genetically at-risk individuals remain promising because the underlying biological and pathological mechanisms are more elucidated [ 49 ], biomarker research is progressing quickly [ 50, 51 ], and at-risk individuals can be identified very early [ 52 ]. In addition, direct-to-consumer genetic testing companies such as 23andMe as well as research initiatives such as PPMI and the Rostock International Parkinson’s Disease Study (ROPAD) have already identified over 4,000 contactable, non-manifesting carriers of the LRRK2 G2019 S variant and even more with pathologic GBA variants [ 53 ].…”

Section: Perspectives Of At-risk Individualsmentioning

confidence: 99%

Perspectives of People At-Risk on Parkinson’s Prevention Research

Keavney,

Mathur,

Schroeder

et al. 2024

Journal of Parkinson’s Disease

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The movement toward prevention trials in people at-risk for Parkinson’s disease (PD) is rapidly becoming a reality. The authors of this article include a genetically at-risk advocate with the LRRK2 G2019 S variant and two patients with rapid eye movement sleep behavior disorder (RBD), one of whom has now been diagnosed with PD. These authors participated as speakers, panelists, and moderators in the “Planning for Prevention of Parkinson’s: A Trial Design Forum” hosted by Massachusetts General Hospital in 2021 and 2022. Other authors include a young onset person with Parkinson’s (PwP) and retired family physician, an expert in patient engagement in Parkinson’s, and early career and veteran movement disorders clinician researchers. Several themes emerged from the at-risk participant voice concerning the importance of early intervention, the legitimacy of their input in decision-making, and the desire for transparent communication and feedback throughout the entire research study process. Challenges and opportunities in the current environment include lack of awareness among primary care physicians and general neurologists about PD risk, legal and psychological implications of risk disclosure, limited return of individual research study results, and undefined engagement and integration of individuals at-risk into the broader Parkinson’s community. Incorporating the perspectives of individuals at-risk as well as those living with PD at this early stage of prevention trial development is crucial to success.

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“…While its complete modes of action are under study, LRRK2 has been shown to act directly on L-type VGCCs (e.g., Cav2.1). Over a dozen mutations in LRRK2 cause an increased risk for PD, but disease penetrance varies widely from ~17 to 80% [144]. Studies on these mutations have generated a deeper understanding of the various PD subgroups that differ from sporadic and inherited forms of the disease.…”

Section: Lrrk2: a Vgcc Regulatormentioning

confidence: 99%

The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration

O’Day

2024

Biomolecules

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Calcium dyshomeostasis is an early critical event in neurodegeneration as exemplified by Alzheimer’s (AD), Huntington’s (HD) and Parkinson’s (PD) diseases. Neuronal calcium homeostasis is maintained by a diversity of ion channels, buffers, calcium-binding protein effectors, and intracellular storage in the endoplasmic reticulum, mitochondria, and lysosomes. The function of these components and compartments is impacted by the toxic hallmark proteins of AD (amyloid beta and Tau), HD (huntingtin) and PD (alpha-synuclein) as well as by interactions with downstream calcium-binding proteins, especially calmodulin. Each of the toxic hallmark proteins (amyloid beta, Tau, huntingtin, and alpha-synuclein) binds to calmodulin. Multiple channels and receptors involved in calcium homeostasis and dysregulation also bind to and are regulated by calmodulin. The primary goal of this review is to show the complexity of these interactions and how they can impact research and the search for therapies. A secondary goal is to suggest that therapeutic targets downstream from calcium dyshomeostasis may offer greater opportunities for success.

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Perspective on the current state of the LRRK2 field

Cited by 50 publications

References 127 publications

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

The landscape of rare genetic variation associated with inflammatory bowel disease and Parkinson’s disease comorbidity

Perspectives of People At-Risk on Parkinson’s Prevention Research

The Complex Interplay between Toxic Hallmark Proteins, Calmodulin-Binding Proteins, Ion Channels, and Receptors Involved in Calcium Dyshomeostasis in Neurodegeneration

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