Insights on LRRK2, gene behind Parkinson’s disease

Varuni Ankolekar, Quartesian

One of the common neurogenerative disorders noticed in elderly populations is Parkinson’s disease that affects movement. Common symptoms are tremor, rigidity, bradykinesia, and postural instability.

Gene behind Parkinson’s disease:

Dysfunction of the Leucine-rich repeat kinase 2 (LRRK2) gene on chromosome 12 has proven to be the cause of Parkinson’s disease. LRRK2 is a Kinase enzyme that is encoded by the LRRK2 gene. LRRK2 gene is widely expressed in the brain and other tissues all over the body. Both autosomal coding mutations and non-coding variations can be seen at the LRRK2 locus. The functional consequences of the non-coding variants are not clear. However, it plays a key factor in Parkinson’s as it indicates the physiological function of LRRK2.

Interpreting atomic-resolution structural data of LRRK2 was challenging due to its large size which is 250 kDa.

Structure of LRRK2:

LRRK2 is a large protein, made up of 2527 amino acids. It comprises several domains which have different functions. The structure of LRRK2 involves Ras of Complex (Roc) GTPase at the center along with the C-terminus of Roc (COR) domain after which serine-threonine kinase domains are observed. Several proteins -protein interactions are noticed with ankyrin and leucine-rich repeat motifs while WD40 repeats at the N-terminus and C-terminus respectively.

LRRK2 structure including individual domains and orthologous proteins:

• In 2008, the structure of the ROC domain was studied in H. sapiens under 2.0 Å resolution using X-ray crystallography by purifying isolated domains and/or exploring orthologous proteins.
• In 2008, the structure of ROC–COR was examined in C. tepidum under 2.90 Å resolution using X-ray crystallography.
• In 2012, the structure of the Kinase domain isolated from D. discoidium was analyzed under 1.8 Å resolution using X-ray crystallography.
• In 2016, the prototype for Full-length LRRK2 was suggested in H. sapiens and LRR in C. tepidum at 33 Å and 2.3 Å resolution with the help of CryoEM and X-ray crystallography respectively.
• In 2017, the structure of Full length in H. sapiens at 24.2 Å resolution using CryoEM was performed.
• In 2019, the model of ROC in H. sapiens at 1.6 Å resolution using X-ray crystallography
• In 2019, the structure of WD40 in H. sapiens 2.6 Å resolution using X-ray crystallography
• In 2019, the structure of LRR–ROC–COR in C. tepidum 3.29 Å resolution using X-ray crystallography. The study so far gave the understandings at the molecular level. However, the impact of mutations is yet to be known.
• In 2020, the structure of ROC–COR–Kinase– WD40 in H. sapiens under 3.50 Å resolution using CryoEM.
• In 2020, the structure of Full-length LRRK2 was proposed H. sapiens 14 Å resolution using CryoEM
• Recently, in 2021, the structure of Full-length LRRK2 was proposed H. sapiens 3.7 Å for monomer and 3.5 Å resolution for a dimer using CryoEM which provided insights on the spatial relationship between LRRK2 domains.

The bottom line is the identification of LRRK2 structures as it has been of interest for several reasons. The recent discovery of full length has uncovered the complex LRRK2 interactions between the domains and gave a bit of clarification on mutations at LRRK2 kinase and LRRK2 ROC– COR domain. Further understandings of the connection between structure and function will be crucial to focus on Parkinson’s while studying the effect of various coding mutations and risk variants observed in LRRK2 associated with Parkinson’s disease.

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Reference:

1. Herbst, S., & Lewis, P. A. (2021). From structure to ætiology: A new window on the biology of leucine-rich repeat kinase 2 and Parkinson’s disease. Biochemical Journal, 478(14), 2945–2951. https://doi.org/10.1042/BCJ20210383

2. Rui, Q., Ni, H., Li, D., Gao, R., & Chen, G. (2018). The role of lrrk2 in neurodegeneration of parkinson disease. Current Neuropharmacology, 16(9), 1348–1357. https://doi.org/10.2174/1570159X16666180222165418

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Author Info: Varuni Ankolekar, Quartesian

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