The Therapeutic Potential of LRRK2 and α-Synuclein in Parkinson's Disease

Sen, Satyabrata; West, Andrew B.

doi:10.1089/ars.2009.2430

Cited by 9 publications

(15 citation statements)

References 279 publications

(333 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with these studies a-synuclein-null mice showed heightened resistance to MPTP and other mitochondrial toxins (17). As indicated above, use of drugs that upregulate chaperones such as Hsp70 to block a-synuclein aggregation has shown efficacy in both in vitro and in vivo models of disease (14,16). Other means to block a-synuclein aggregation includes use of synthetic peptides derived from the N-terminal amino acid sequence of a-synuclein, and human single-chain antibody fragments (scFv) that binds a-synuclein to inhibit formation of toxic a-synuclein fibrils.…”

Section: Infiltration Of T Cells Has Been Found In Brains Of Pd Patiesupporting

confidence: 66%

“…Interestingly flies expressing wild-type dLRRK or dLRRK2 with mutations predicted to inactivate kinase activity failed to develop dopaminergic toxicity. This in vivo study suggests that the LRRK2 kinase activity could serve as a valid target for neuroprotection for PD, although additional studies will be required from multiple in vivo models to definitively prove that LRRK2 kinase activity is indeed an ideal target for drug development (14).…”

Section: Thomasmentioning

confidence: 89%

“…Identification of two autosomal dominant forms of PD due to gain of function mutations in a-synuclein and LRRK2 gene and the current understanding of the functions of these two molecules suggests they might serve as possible avenue for target validation for PD therapeutics (14). The presence of a-synuclein as a major component of LB, familial a-synuclein mutations, gene multiplication, and protein misfolding suggests that toxic accumulation of a-synuclein plays a pathogenic role in PD.…”

Section: Infiltration Of T Cells Has Been Found In Brains Of Pd Patiementioning

confidence: 99%

“…The notion of LRRK2 as a potential drugable target in PD has originated from its resemblance to a ''kinase'' bearing structural similarity to mixed lineage kinases (14,17). There are several missense mutations in the LRRK2 gene identified to be associated with PD, of which the G2019S mutation is the most prevalent.…”

Section: Thomasmentioning

confidence: 99%

See 3 more Smart Citations

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Thomas

2009

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Parkinson's disease (PD) is a complex multifactor disease marked by extensive neuropathology in the brain with selective yet prominent and progressive loss of midbrain dopamine neurons. Clinically PD is characterized by motor abnormalities including resting tremor, bradykinesia, altered gait, muscular rigidity, postural instability, together with autonomic dysfunctions. The etiological factors involved in the development of PD are still elusive, but there is considerable evidence that a combination of genetic susceptibilities and environmental factors plays a critical role in disease pathogenesis. The identification of single genes in the past decade linked to heritable forms of PD has challenged the previously held view of a nongenetic etiology for this progressive movement disorder. These genetic breakthroughs have revolutionized the research by providing unique opportunities to pursue novel mechanisms and identified new clues to disease pathogenesis in PD. This forum review provides an update on current hypotheses and recent findings in mitochondrial dysfunction, oxidative damage, innate and adaptive immune systems, protein misfolding and aggregation, and advances in translational approaches to PD. These aspects are reviewed with an aim to promote better understanding of molecular pathways prevalent in parkinsonian brain that will eventually aide in development of promising therapeutic strategies.

show abstract

Section: Infiltration Of T Cells Has Been Found In Brains Of Pd Patiesupporting

confidence: 66%

Section: Thomasmentioning

confidence: 89%

Section: Infiltration Of T Cells Has Been Found In Brains Of Pd Patiementioning

confidence: 99%

Section: Thomasmentioning

confidence: 99%

See 2 more Smart Citations

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Thomas

2009

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…Pathological mutations in the LRRK2 protein often cause phenotypes similar to the more prevalent idiopathic late-onset PD, suggesting a shared etiology between the two diseases 39 . The most straightforward approach to hone in on the pathogenic activity associated with LRRK2 may lie in successful identification of the difference between mutant and WT protein.…”

Section: Discussionmentioning

confidence: 99%

Autophosphorylation in the Leucine-Rich Repeat Kinase 2 (LRRK2) GTPase Domain Modifies Kinase and GTP-Binding Activities

Webber

Smith

Sen

et al. 2011

Journal of Molecular Biology

Self Cite

120

152

View full text Add to dashboard Cite

The LRRK2 protein has both GTPase and kinase activities and mutation in either enzymatic domain can cause late-onset Parkinson’s disease (PD). Nucleotide binding in the GTPase domain may be required for kinase activity and residues in the GTPase domain are potential sites for autophosphorylation, suggesting a complex mechanism of intrinsic regulation. To further define the effects of LRRK2 autophosphorylation, we applied a technique optimal for detection of protein phosphorylation, electron transfer dissociation (ETD), and identified autophosphorylation events exclusively nearby the nucleotide binding pocket in the GTPase domain. PD-linked mutations alter kinase activity but did not alter autophosphorylation site specificity or sites of phosphorylation in a robust in vitro substrate myelin basic protein. Amino-acid substitutions in the GTPase domain have large effects on kinase activity, as insertion of the GTPase-associated R1441C pathogenic mutation together with the G2019S kinase-domain mutation resulted in a multiplicative increase (~7-fold) in activity. Removal of a conserved autophosphorylation site (T1503) by mutation to an alanine residue resulted in greatly decreased GTP-binding and kinase activity. While autophosphorylation likely serves to potentiate kinase activity, we find that oligomerization and loss of the active dimer species occurs in an ATP and autophosphorylation independent manner. LRRK2 autophosphorylation sites are overall robustly protected from dephosphorylation in vitro, suggesting tight control over activity in vivo. We developed highly specific antibodies targeting pT1503 but failed to detect endogenous autophosphorylation in protein derived from transgenic mice and cell lines. LRRK2 activity in vivo is unlikely to be constitutive but rather refined to specific responses.

show abstract

Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease

et al. 2018

View full text Add to dashboard Cite

IMPORTANCE Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. OBJECTIVE To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. DESIGN, SETTING, AND PARTICIPANTS To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. MAIN OUTCOMES AND MEASURES Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. RESULTS Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. CONCLUSIONS AND RELEVANCE Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.

show abstract

The Therapeutic Potential of LRRK2 and α-Synuclein in Parkinson's Disease

Cited by 9 publications

References 279 publications

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Parkinson's Disease: From Molecular Pathways in Disease to Therapeutic Approaches

Autophosphorylation in the Leucine-Rich Repeat Kinase 2 (LRRK2) GTPase Domain Modifies Kinase and GTP-Binding Activities

Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease

Contact Info

Product

Resources

About