LRRK2 Pathways Leading to Neurodegeneration

Cookson, Mark

doi:10.1007/s11910-015-0564-y

Cited by 121 publications

(113 citation statements)

References 99 publications

Supporting

Mentioning

110

Contrasting

Order By: Relevance

“…This differential recovery of PPIs is likely driven by literature bias toward proteins with known human disease associations. For example, LRRK2 is the focus of many investigations within PD research, [38] whereas MASL1 is relatively understudied. [21] Interestingly, this trend differs when considering the interactomes prior to applying the confidence threshold (i.e., when retaining all reported interactors regardless of replication; Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Tomkins

Dihanich²,

Beilina

et al. 2018

Proteomics

Self Cite

View full text Add to dashboard Cite

Signal transduction cascades governed by kinases and GTPases are a critical component of the command and control of cellular processes, with the precise outcome partly determined by direct protein–protein interactions (PPIs). Here, we use the human ROCO proteins as a model for investigating PPI signaling events—taking advantage of the unique dual kinase/GTPase activities and scaffolding properties of these multidomain proteins. PPI networks are reported that encompass the human ROCO proteins, developed using two complementary approaches. First, using the recently developed weighted PPI network analysis (WPPINA) pipeline, a confidence-weighted overview of validated ROCO protein interactors is obtained from peer-reviewed literature. Second, novel ROCO PPIs are assessed experimentally via protein microarray screens. The networks derived from these orthologous approaches are compared to identify common elements within the ROCO protein interactome; functional enrichment analysis of this common core of the network identified stress response and cell projection organization as shared functions within this protein family. Despite the presence of these commonalities, the results suggest that many unique interactors and therefore some specialized cellular roles have evolved for different members of the ROCO proteins. Overall, this multi-approach strategy to increase the resolution of protein interaction networks represents a prototype for the utility of PPI data integration in understanding signaling biology.

show abstract

Section: Resultsmentioning

confidence: 99%

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Tomkins

Dihanich²,

Beilina

et al. 2018

Proteomics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mutations in LRRK2 are collectively the most common genetic cause of PD, associated with both familial and sporadic cases (Nalls et al, 2014; Paisan-Ruiz et al, 2004; Satake et al, 2009; Simon-Sanchez et al, 2009; Zimprich et al, 2004), highlighting the importance of LRRK2 in PD pathogenesis (Cookson, 2015; Pan and Yue, 2014; Tsika and Moore, 2012). Genetic analysis revealed striking age-dependent autophagy impairment and accumulation of a-synuclein as well as increases of apoptosis in the LRRK2 −/− kidney (Tong et al, 2012; Tong et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

Giaime

Tong

Wagner

et al. 2017

Neuron

104

103

View full text Add to dashboard Cite

Summary LRRK2 mutations are the most common genetic cause of Parkinson’s disease, but its normal physiological role in the brain is unclear. Here we show that inactivation of LRRK2 and its functional homologue LRRK1 results in earlier mortality and age-dependent, selective neurodegeneration. Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and noradrenergic neurons in the locus coeruleus is accompanied with increases in apoptosis, whereas the cerebral cortex and cerebellum are unaffected. Furthermore, selective age-dependent neurodegeneration is only present in LRRK−/− but not LRRK1−/− or LRRK2−/− brains, and is accompanied with increases of α-synuclein and impairment of the autophagy-lysosomal pathway. Quantitative electron microscopy analysis revealed age-dependent increases of autophagic vacuoles in the SNpc of LRRK−/− mice before the onset of dopaminergic neuron loss. These findings revealed an essential role of LRRK in the survival of dopaminergic neurons and the regulation of the autophagy-lysosomal pathway in the aging brain.

show abstract

“…To date, five mutations in LRRK2 have been shown unambiguously to segregate with familial PD and two additional variants have been nominated as risk factors (reviewed in [11, 12]). All of these LRRK2 mutations show age-dependent incomplete penetrance, meaning that some LRRK2 mutation carriers do not show clinical phenotypes during their lifetime [13]. …”

Section: Lrrk2 Is In a Pleomorphic Risk Locus For Pdmentioning

confidence: 99%

“…1) and mutated proteins have altered biochemical activity in vitro [17]. There are subtle differences between mutations, as the kinase domain mutations including G2019S and I2020T directly increase kinase activity [13] whereas those in the ROC-COR domains, the best studied of which are R1441C/G and Y1699C, decrease GTPase activity [18–21]. However, it is thought that the physical proximity of two enzyme activities encoded in the same protein structure implies that they regulate each other and lead to a co-ordinated output in cellular signaling [22, 23].…”

Section: Lrrk2 Structure and Enzymatic Domainsmentioning

confidence: 99%

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

Roosen

Cookson

2016

Mol Neurodegeneration

Self Cite

152

127

View full text Add to dashboard Cite

Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson’s disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases.

show abstract

LRRK2 Pathways Leading to Neurodegeneration

Cited by 121 publications

References 99 publications

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Comparative Protein Interaction Network Analysis Identifies Shared and Distinct Functions for the Human ROCO Proteins

Age-Dependent Dopaminergic Neurodegeneration and Impairment of the Autophagy-Lysosomal Pathway in LRRK-Deficient Mice

LRRK2 at the interface of autophagosomes, endosomes and lysosomes

Contact Info

Product

Resources

About