LRRK 2 gene mutations in the pathophysiology of the ROCO domain and therapeutic targets for Parkinson's disease: A review Julie Y.H. Chan
Journal
Journal of Biomedical Science
Journal Volume
25
Journal Issue
1
Pages
52
Date Issued
2018
Author(s)
Chen M.-L
Abstract
Parkinson's disease (PD) is the most common movement disorder and manifests as resting tremor, rigidity, bradykinesia, and postural instability. Pathologically, PD is characterized by selective loss of dopaminergic neurons in the substantia nigra and the formation of intracellular inclusions containing α-synuclein and ubiquitin called Lewy bodies. Consequently, a remarkable deficiency of dopamine in the striatum causes progressive disability of motor function. The etiology of PD remains uncertain. Genetic variability in leucine-rich repeat kinase 2 (LRRK2) is the most common genetic cause of sporadic and familial PD. LRRK2 encodes a large protein containing three catalytic and four protein-protein interaction domains. Patients with LRRK2 mutations exhibit a clinical and pathological phenotype indistinguishable from sporadic PD. Recent studies have shown that pathological mutations of LRRK2 can reduce the rate of guanosine triphosphate (GTP) hydrolysis, increase kinase activity and GTP binding activity, and subsequently cause cell death. The process of cell death involves several signaling pathways, including the autophagic-lysosomal pathway, intracellular trafficking, mitochondrial dysfunction, and the ubiquitin-proteasome system. This review summarizes the cellular function and pathophysiology of LRRK2 ROCO domain mutations in PD and the perspective of therapeutic approaches. ? 2018 The Author(s).
Subjects
GTPase activity; LRRK2; Parkinson's disease; ROCO domain; Signaling pathway
SDGs
Other Subjects
alpha synuclein; antiparkinson agent; dopamine; guanosine triphosphate; leucine rich repeat kinase 2; leucine rich repeat kinase 2 inhibitor; phosphotransferase; phosphotransferase inhibitor; proteasome; ubiquitin; unclassified drug; dopamine; leucine rich repeat kinase 2; LRRK2 protein, human; body position; bradykinesia; cell inclusion; cell loss; clinical feature; corpus striatum; diffuse Lewy body disease; disease course; disorders of mitochondrial functions; dopaminergic nerve cell; enzyme activity; familial disease; gene activity; gene mutation; genetic association; genetic variability; human; hydrolysis; intracellular transport; LRRK2 gene; lysosome; molecular pathology; motor dysfunction; nerve cell necrosis; nonhuman; Parkinson disease; phenotype; priority journal; protein domain; protein protein interaction; protein structure; Review; rigidity; ROC domain; ROCO domain; signal transduction; substantia nigra; tremor; genetics; metabolism; mutation; Parkinson disease; pathology; protein domain; Dopamine; Dopaminergic Neurons; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Parkinson Disease; Protein Domains; Substantia Nigra
Type
review