scholarly journals Increased LRRK2 kinase activity alters neuronal autophagy by disrupting the axonal transport of autophagosomes

2021 ◽  
Author(s):  
C. Alexander Boecker ◽  
Juliet Goldsmith ◽  
Dan Dou ◽  
Gregory G. Cajka ◽  
Erika L.F. Holzbaur
Keyword(s):  
Axonal Transport ◽  
Kinase Activity ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity ◽  
Neuronal Autophagy

scholarly journals Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein

2021 ◽  
Author(s):  
Charlotte F Brzozowski ◽  
Baraa A Hijaz ◽  
Vijay Singh ◽  
Nolwazi Z Gcwensa ◽  
Kaela Kelly ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Kinase Activity ◽  
Alpha Synuclein ◽  
Presynaptic Terminal ◽  
Lewy Pathology ◽  
Anterograde Axonal Transport ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

Pathologic inclusions composed of alpha-synuclein called Lewy pathology are hallmarks of Parkinson Disease (PD). Dominant inherited mutations in leucine rich repeat kinase 2 (LRRK2) are the most common genetic cause of PD. Lewy pathology is found in the majority of individuals with LRRK2-PD, particularly those with the G2019S-LRRK2 mutation. Lewy pathology in LRRK2-PD associates with increased non-motor symptoms such as cognitive deficits, anxiety, and orthostatic hypotension. Thus, understanding the relationship between LRRK2 and alpha-synuclein could be important for determining the mechanisms of non-motor symptoms. In PD models, expression of mutant LRRK2 reduces membrane localization of alpha-synuclein, and enhances formation of pathologic alpha-synuclein, particularly when synaptic activity is increased. alpha-Synuclein and LRRK2 both localize to the presynaptic terminal. LRRK2 plays a role in membrane traffic, including axonal transport, and therefore may influence alpha-synuclein synaptic localization. This study shows that LRRK2 kinase activity influences alpha-synuclein targeting to the presynaptic terminal. We used the selective LRRK2 kinase inhibitors, MLi-2 and PF-06685360 (PF-360) to determine the impact of reduced LRRK2 kinase activity on presynaptic localization of alpha-synuclein. Expansion microscopy (ExM) in primary hippocampal cultures and the mouse striatum, in vivo, was used to more precisely resolve the presynaptic localization of alpha-synuclein. Live imaging of axonal transport of alpha-synuclein-GFP was used to investigate the impact of LRRK2 kinase inhibition on alpha-synuclein axonal transport towards the presynaptic terminal. Reduced LRRK2 kinase activity increases alpha-synuclein overlap with presynaptic markers in primary neurons, and increases anterograde axonal transport of alpha-synuclein-GFP. In vivo, LRRK2 inhibition increases alpha-synuclein overlap with glutamatergic, cortico-striatal terminals, and dopaminergic nigral-striatal presynaptic terminals. The findings suggest that LRRK2 kinase activity plays a role in axonal transport, and presynaptic targeting of alpha-synuclein. These data provide potential mechanisms by which LRRK2-mediated perturbations of alpha-synuclein localization could cause pathology in both LRRK2-PD, and idiopathic PD.

scholarly journals Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection

Cell Research ◽  
2019 ◽  
Vol 29 (4) ◽  
pp. 313-329 ◽  
Author(s):  
Adam Schaffner ◽  
Xianting Li ◽  
Yacob Gomez-Llorente ◽  
Emmanouela Leandrou ◽  
Anna Memou ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Vitamin B12 ◽  
Kinase Activity ◽  
Allosteric Regulation ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Ser1292 Autophosphorylation Is an Indicator of LRRK2 Kinase Activity and Contributes to the Cellular Effects of PD Mutations

2012 ◽  
Vol 4 (164) ◽  
pp. 164ra161-164ra161 ◽  
Author(s):  
Z. Sheng ◽  
S. Zhang ◽  
D. Bustos ◽  
T. Kleinheinz ◽  
C. E. Le Pichon ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Cellular Effects ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Measurement of LRRK2 Kinase Activity by Proximity Ligation Assay

BIO-PROTOCOL ◽  
2021 ◽  
Vol 11 (17) ◽  
Author(s):  
Matthew Keeney ◽  
Eric Hoffman ◽  
J. Greenamyre ◽  
Roberto Di Maio
Keyword(s):  
Kinase Activity ◽  
Proximity Ligation Assay ◽  
Proximity Ligation ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Phosphorylation of LRRK2: from kinase to substrate

2012 ◽  
Vol 40 (5) ◽  
pp. 1102-1110 ◽  
Author(s):  
Evy Lobbestael ◽  
Veerle Baekelandt ◽  
Jean-Marc Taymans
Keyword(s):  
Kinase Activity ◽  
Pathological Process ◽  
Rapid Decrease ◽  
Leucine Rich Repeat ◽  
Phosphorylated Protein ◽  
Pathogenic Variants ◽  
Disease Protein ◽  
Lrrk2 Kinase ◽  
Disease Modifying ◽  
Lrrk2 Kinase Activity

The PD (Parkinson's disease) protein LRRK2 (leucine-rich repeat kinase 2) occurs in cells as a highly phosphorylated protein, with the majority of phosphosites clustering in the region between the ankyrin repeat and leucine-rich repeat domains. The observation that several pathogenic variants of LRRK2 display strongly reduced cellular phosphorylation suggests that phosphorylation of LRRK2 is involved in the PD pathological process. Furthermore, treatment of cells with inhibitors of LRRK2 kinase activity, which are currently considered as potential disease-modifying therapeutics for PD, leads to a rapid decrease in the phosphorylation levels of LRRK2. For these reasons, understanding the cellular role and regulation of LRRK2 as a kinase and as a substrate has become the focus of intense investigation. In the present review, we discuss what is currently known about the cellular phosphorylation of LRRK2 and how this relates to its function and dysfunction.

scholarly journals Inhibitory role of peroxiredoxin 2 in LRRK2 kinase activity induced cellular pathogenesis

2020 ◽  
Vol 34 (2) ◽  
pp. 103
Author(s):  
Kang Yan ◽  
◽  
◽  
Wenfeng Zhang ◽  
Xu Han ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Peroxiredoxin 2 ◽  
Inhibitory Role ◽  
Lrrk2 Kinase ◽  
Cellular Pathogenesis ◽  
Lrrk2 Kinase Activity

scholarly journals The activities of LRRK2 and GCase are positively correlated in clinical biospecimens and experimental models of Parkinson’s disease

2021 ◽  
Author(s):  
Maria Kedariti ◽  
Emanuele Frattini ◽  
Pascale Baden ◽  
Susanna Cogo ◽  
Laura Civiero ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Experimental Models ◽  
Cellular Functions ◽  
Gene Encoding ◽  
Cellular Models ◽  
Lrrk2 Kinase ◽  
The Impact ◽  
Lrrk2 Kinase Activity

AbstractLRRK2 is a kinase involved in different cellular functions, including autophagy, endolysosomal pathways and vesicle trafficking. Mutations in LRRK2 cause autosomal dominant forms of Parkinson’s disease (PD). Heterozygous mutations in GBA1, the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), are the most common genetic risk factors for PD. Moreover, GCase function is altered in idiopathic PD and in other genetic forms of the disease. Recent work suggests that LRRK2 kinase activity can regulate GCase function. However, both a positive and a negative correlation have been described. To gain insights into the impact of LRRK2 on GCase, we investigated GCase levels and activity in LRRK2 G2019S knockin mice, in clinical biospecimens from PD patients carrying this mutation and in patient-derived cellular models. In these models we found a positive correlation between the activities of LRRK2 and GCase, which was further confirmed in cell lines with genetic and pharmacological manipulation of LRRK2 kinase activity. Overall, our study indicates that LRRK2 kinase activity affects both the levels and the catalytic activity of GCase.

Role of LRRK2 kinase activity in the pathogenesis of Parkinson's disease

2012 ◽  
Vol 40 (5) ◽  
pp. 1058-1062 ◽  
Author(s):  
Elisa Greggio
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Kinase Activity ◽  
Complex Molecule ◽  
Disease Onset ◽  
Missense Mutations ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity

Interest in studying the biology of LRRK2 (leucine-rich repeat kinase 2) started in 2004 when missense mutations in the LRRK2 gene were linked to an inherited form of Parkinson's disease with clinical and pathological presentation resembling the sporadic syndrome. LRRK2 is a complex molecule containing domains implicated in protein interactions, as well as kinase and GTPase activities. The observation that the common G2019S mutation increases kinase activity in vitro suggests that altered phosphorylation of LRRK2 targets may have pathological outcomes. Given that protein kinases are ideal targets for drug therapies, much effort has been directed at understanding the role of LRRK2 kinase activity on disease onset. However, no clear physiological substrates have been identified to date, indicating that much research is still needed to fully understand the signalling pathways orchestrated by LRRK2 and deregulated under pathological conditions.

scholarly journals 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening

2015 ◽  
Vol 25 (1) ◽  
pp. 109-122 ◽  
Author(s):  
Nicholas J. Lavalley ◽  
Sunny R. Slone ◽  
Huiping Ding ◽  
Andrew B. West ◽  
Talene A. Yacoubian
Keyword(s):  
Kinase Activity ◽  
Mutant Lrrk2 ◽  
Lrrk2 Kinase ◽  
Lrrk2 Kinase Activity
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