Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease

Aasly, Jan; Vilariño‐Güell, Carles; Dächsel, Justus C.; Webber, Philip J.; West, Andrew B.; Haugarvoll, Kristoffer; Johansen, Krisztina K.; Toft, Mathias; Nutt, John G.; Payami, Haydeh; Kachergus, Jennifer M.; Lincoln, Sarah; Felic, Amela; Wider, Christian; Soto‐Ortolaza, Alexandra I.; Cobb, Stephanie A.; White, Linda R.; Ross, Owen A.; Farrer, Matthew J.

doi:10.1002/mds.23265

Cited by 111 publications

(95 citation statements)

References 19 publications

(23 reference statements)

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“…This suggests that the G2019S mutation plays a significant role in PD pathogenesis and is a risk factor for sporadic PD. In contrast, the N1437H mutation has only been reported in 2 Norwegian families [35] and 1 Swedish patient with PD [36]. These mutations have a common characteristic: they are located in catalytically active domains.…”

Section: Lrrk2 Mutations and Their Mechanisms Of Actionmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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Background: Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. Summary: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment.

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Section: Lrrk2 Mutations and Their Mechanisms Of Actionmentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Chen¹,

Chen²,

Pu³

2018

Eur Neurol

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“…1; Table 1) [48,58,59]. Some additional LRRK2 variants represent risk factors for the disease (G2385R, R1628P), while the role of other reported substitutions remains unclear.…”

Section: Diversity Of Lrrk2 Mutationsmentioning

confidence: 99%

“…The N1437H substitution was found in 2 Norwegian families and 1 patient from Sweden [58,104]. Owing to the limited genetic data, whether this mutation is pathogenic is uncertain.…”

Section: Lrrk2 Polymorphisms That May Affect Protein Functionmentioning

confidence: 99%

“…Owing to the limited genetic data, whether this mutation is pathogenic is uncertain. Direct evaluation of GTPase and kinase activity of N1437H LRRK2 has not yet been reported, although this variant does cause increased GTP binding [58]. When overexpressed in HEK293 cells, N1437H LRRK2 has an increased phosphorylation at Ser1292 [105] and diminished phosphorylation of Ser935 and, hence, 14-3-3 binding [92].…”

Section: Lrrk2 Polymorphisms That May Affect Protein Functionmentioning

confidence: 99%

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Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Rudenko

Cookson

2014

Neurotherapeutics

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Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

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“…3). A number of novel variants have been identified in this gene in PD patients, but only seven of these (N1437H, R1441C, R1441G, S1761R, Y1699C, G2019S, and I2020T) can be considered as definitively disease causing, on the basis of co-segregation with disease in families, and an absence in controls [5,[11][12][13]. These mutations either lead to an increased kinase activity (G2019S and I2020T) or to a reduced GTPase activity (R1441C/G and Y1699C), which in turn regulates kinase activity [14][15][16] (vide infra).…”

Section: Lrrk2 Genetics and Human Biologymentioning

confidence: 99%

Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors

Galatsis

Henderson

Kormos

et al. 2014

Topics in Medicinal Chemistry

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Mutations in the leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of autosomal dominant Parkinson's disease (PD), accounting for approximately 1% of "sporadic" and 4% of familial cases. These mutations either lead directly to an increased kinase activity (G2019S and I2020T are in the kinase activation loop) or to a reduced GTPase activity (R1441C/G and Y1699C), that in turn positively regulate kinase activity. The physiological substrate of the LRRK2 kinase has yet to be definitively identified, yet autophosphorylation is emerging as a relatively robust measure of its activity. LRRK2 has been implicated in a number of diverse cellular processes such as vesicular trafficking, microtubule dynamics, protein translation control, inflammation, and immune function, all of which have been linked to PD. LRRK2 is a large, multi-domain protein; a thorough understanding of the protein domain organization and identification of interacting partners is important to determine the underlying mechanism of LRRK2. Substantial recent effort has been directed towards identifying potent LRRK2 kinase inhibitors, from the repurposed kinase inhibitors to the first through third generation of LRRK2-focused kinase inhibitors, from a range of chemotypes, which are now providing researchers with new tools to better interrogate LRRK2 function.

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Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease

Cited by 111 publications

References 19 publications

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Leucine-Rich Repeat Kinase 2 in Parkinson’s Disease: Updated from Pathogenesis to Potential Therapeutic Target

Heterogeneity of Leucine-Rich Repeat Kinase 2 Mutations: Genetics, Mechanisms and Therapeutic Implications

Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors

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