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Review
. 2024 Oct 30;25(21):11661.
doi: 10.3390/ijms252111661.

CK and LRRK2 Involvement in Neurodegenerative Diseases

Affiliations
Review

CK and LRRK2 Involvement in Neurodegenerative Diseases

Valentina Bova et al. Int J Mol Sci. .

Abstract

Neurodegenerative diseases (NDDs) are currently the most widespread neuronal pathologies in the world. Among these, the most widespread are Alzheimer's disease (AD), dementia, Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD)-all characterized by a progressive loss of neurons in specific regions of the brain leading to varied clinical symptoms. At the basis of neurodegenerative diseases, an emerging role is played by genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene that cause increased LRRK2 activity with consequent alteration of neuronal autophagy pathways. LRRK2 kinase activity requires GTPase activity which functions independently of kinase activity and is required for neurotoxicity and to potentiate neuronal death. Important in the neurodegeneration process is the upregulation of casein kinase (CK), which causes the alteration of the AMPK pathway by enhancing the phosphorylation of α-synuclein and huntingtin proteins, known to be involved in PD and HD, and increasing the accumulation of the amyloid-β protein (Aβ) for AD. Recent research has identified CK of the kinases upstream of LRRK2 as a regulator of the stability of the LRRK2 protein. Based on this evidence, this review aims to understand the direct involvement of individual kinases in NDDs and how their crosstalk may impact the pathogenesis and early onset of neurodegenerative diseases.

Keywords: casein kinases; degradative pathways; leucine riche-repeat kinase; neurodegeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Autophagy and apoptosis diagrams. (A) Misfolded protein aggregates are tagged with ubiquitin chains, recognized by receptors such as SQSTM1/p62 and optineurin (OPTN). These receptors link ubiquitinated cargo to autophagosomes by interacting with the autophagosome-associated protein LC3, facilitating selective degradation. (B) The process of apoptosis is initiated by signals involving proteins of the Bcl-2 family. Proapoptotic proteins, such as Bax, promote the permeabilization of the outer mitochondrial membrane. This leads to the activation of proapoptotic molecules, such as caspases, which determine the controlled degradation of damaged cells.
Figure 2
Figure 2
Structure of CK1δ. The structure is composed of two main domains: a small N-lobe and a large C-lobe. The N-lobe is composed mainly of β-sheets, while the C-lobe is composed predominantly of α-helices. These two lobes are essential for the formation of the catalytic cleft, which is the active site where CK1δ binds to ATP and its target substrates. This cleft facilitates kinase activity by allowing the transfer of a phosphate group from ATP to the substrate, thereby regulating various cellular processes [77].
Figure 3
Figure 3
Structure of CK2. The structure is composed of two catalytic subunits α/α’ shown in blue and yellow and and two regulatory β subunits shown in green and red. The catalytic α/α’ subunits have an N lobe made up of β-sheets and a C lobe containing α-helices. Between these two lobes is the catalytic cleft where ATP binds to facilitate phosphorylation. The regulatory β subunits have no kinase activity but play a key role in stabilizing the enzyme [95].
Figure 4
Figure 4
Interplay between CKs and LRRK2 in neurodegenerative diseases. (A) This panel represents how casein kinase increases LRRK2 phosphorylation. Hyperphosphorylation of the LRRK2 protein determines an increase in oxidative stress with a compromised autophagic process. (B) This panel represents the onset of neurodegenerative diseases following hyperactivation of LRRK2 and/or mutation of the G2019S gene.

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