CADPS2 gene expression is oppositely regulated by LRRK2 and alpha-synuclein

Obergasteiger, Julia; Überbacher, Christa; Pramstaller, Peter P.; Hicks, Andrew A.; Corti, Corrado; Volta, Mattia

doi:10.1016/j.bbrc.2017.06.134

Cited by 18 publications

(23 citation statements)

References 32 publications

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“…Of note, WT-LRRK2 cells display stronger LRRK2 expression than G2019S-LRRK2 ones (Supplementary Fig. S3 and our previous work 33 ), suggesting pS129-aSyn accumulation is not solely a direct consequence of enhanced LRRK2 expression.…”

Section: Autophagy Alterations In G2019s-lrrk2 Cells Exhibiting Ps129supporting

confidence: 56%

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

et al. 2020

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The Parkinson's disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a crucial modulator of the autophagy-lysosome pathway, but unclarity exists on the precise mechanics of its role and the direction of this modulation. In particular, LRRK2 is involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and a significant proportion of LRRK2 patients presenting Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alphasynuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to obtain a comprehensive knowledge on LRRK2-associated pathology. Here, we investigated a G2019S-LRRK2 recombinant cell line exhibiting accumulation of endogenous, phosphorylated alpha-synuclein. We found that G2019S-LRRK2 leads to accumulation of LC3 and abnormalities in lysosome morphology and proteolytic activity in a kinase-dependent fashion, but independent from constitutively active Rab10. Notably, LRRK2 inhibition was ineffective upon upstream blockade of autophagosome-lysosome fusion events, highlighting this step as critical for alpha-synuclein clearance.

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Section: Autophagy Alterations In G2019s-lrrk2 Cells Exhibiting Ps129supporting

confidence: 56%

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

et al. 2020

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“…Additionally, another study has suggested that dopamine homeostasis and neurotransmitter release may be controlled by α -synuclein level [ 11 ]. Moreover, it was recently reported that the abnormal levels of α -synuclein could affect CADPS2 mRNA expression, causing alterations to synaptic functions [ 30 ]. Therefore, we hypothesize that neural overconnectivity and synapse alteration reported in the pathogenesis of ASD might result from abnormal levels of α -synuclein.…”

Section: Discussionmentioning

confidence: 99%

Significant Changes in Plasma Alpha-Synuclein and Beta-Synuclein Levels in Male Children with Autism Spectrum Disorder

Sriwimol

Limprasert

2018

BioMed Research International

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Alpha-synuclein (α-synuclein) and beta-synuclein (β-synuclein) are presynaptic proteins playing important roles in neuronal plasticity and synaptic vesicle regulation. To evaluate the association of these two proteins and autism spectrum disorder (ASD), we investigated the plasma α-synuclein and β-synuclein levels in 39 male children with ASD (2 subgroups: 25 autism and 14 pervasive developmental disorder-not otherwise specified (PDD-NOS)) comparing with 29 sex- and age-matched controls by using enzyme-linked immunosorbent assay (ELISA). We first determined the levels of these two proteins in the ASD subgroups and found that there were no significant differences in both plasma α-synuclein and β-synuclein levels in the autism and PDD-NOS groups. Thus, we could combine the 2 subgroups into one ASD group. Interestingly, the mean plasma α-synuclein level was significantly lower (P < 0.001) in the ASD children (10.82 ± 6.46 ng/mL) than in the controls (29.47 ± 18.62 ng/mL), while the mean plasma β-synuclein level in the ASD children (1344.19 ± 160.26 ng/mL) was significantly higher (P < 0.05) than in the controls (1219.16 ± 177.10 ng/mL). This is the first study examining the associations between α-synuclein and β-synuclein and male ASD patients. We found that alterations in the plasma α-synuclein and β-synuclein levels might be implicated in the association between synaptic abnormalities and ASD pathogenesis.

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“…Thus, a dynamic balance between these pathways could represent an additional (or even synergistic) factor in pathogenesis. Of note, our WT-LRRK2 cells express higher levels of the protein when compared to G2019S-LRRK2 cells 29 , thus it is plausible to expect that cellular processes might be altered. However, kinase activity is overactive in mutant cells despite the difference in total protein content, indicating that cellular processes are more profoundly affected by aberrant enzyme function.…”

Section: Discussionmentioning

confidence: 88%

“…SH-SY5Y neuroblastoma cell lines stably overexpressing wild-type (WT) or G2019S-LRRK2 were previously described (herein referred to as WT-LRRK2 cells and G2019S-LRRK2 cells) 29,30 . Control SH-SY5Y cells were maintained in DMEM GlutaMAX medium, supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin, while recombinant LRRK2 cells were cultured in DMEM GlutaMAX with 15% FBS, 1% non-essential amino acids, 50 μg/ml gentamycin (Gibco) and 200 μg/ml hygromycin B (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

Obergasteiger

Frapporti

Lamonaca

et al. 2019

Preprint

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words)The Parkinson´s disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a potent modulator of autophagy and impacts on lysosome biology and function, but unclarity exists on the precise mechanics of its role and the direction of this modulation. LRRK2 is also involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and most LRRK2 familial cases manifesting with Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to reconcile these independent pieces of information to obtain a comprehensive knowledge on LRRK2-associated pathology that could also be generalized to the idiopathic disease. Here, we report a focused investigation on the role of PD-causing G2019S-LRRK2 in the autophagy-lysosome pathway in a recombinant cell line model. Initially, we evaluated the effect of LRRK2 expression on autophagy-related transcriptome. Then, we found that G2019S-LRRK2 leads to accumulation of autophagosomes with no net effect on autophagy induction. This is linked to abnormalities in lysosome morphology and proteolytic activity that are associated with a decrease in the successful formation of autolysosomes. Despite some of these features being shared by WT-LRRK2, alpha-synuclein intracellular inclusions are specifically found in G2019S-LRRK2 cells. Pharmacological kinase inhibition is capable of rescuing defects in the autophagy-lysosome pathway and reducing the number of inclusions. Notably, this effect is prevented by upstream blockade of autophagosome-lysosome fusion events, highlighting this step of the process as critical for alpha-synuclein clearance. Mutations in the Lrrk2 gene cause late-onset, familial Parkinson´s disease (PD) with variable penetrance that is clinically indistinguishable from idiopathic PD (iPD) but with pleomorphic pathology 1 . However, the G2019S mutation is singularly the most common genetic cause of PD worldwide, with an incidence up to 40% in specific populations 2,3 , and mostly presents with alpha-synuclein (aSyn) Lewy neuropathology at autopsy 4 . The gene codes for Leucine-Rich Repeat Kinase 2 (LRRK2), a large multidomain protein with two distinct enzymatic domains (GTPase and kinase) in close vicinity to each other 5 . The PDlinked mutations reside in this enzymatic core with G2019S located in the kinase domain and reported to increase kinase activity 6 . The cellular roles impacted by LRRK2 are varied, with stronger consensus on synaptic transmission 7 , vesicle trafficking 8 and autophagy 9 . Interestingly, these pathways might converge in neuronal biology and function 10 . Several independent investigations demonstrated that LRRK2 acts at different stages of the autophagy-lysosome pathway, with some conflicting results on the direction of this modulation 9 . Indications include a kinase-dependent role of LRRK2 in the modulation of...

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CADPS2 gene expression is oppositely regulated by LRRK2 and alpha-synuclein

Cited by 18 publications

References 32 publications

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

Kinase inhibition of G2019S-LRRK2 enhances autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

Significant Changes in Plasma Alpha-Synuclein and Beta-Synuclein Levels in Male Children with Autism Spectrum Disorder

Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

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