LRRK2 phosphorylates pre-synaptic N-ethylmaleimide sensitive fusion (NSF) protein enhancing its ATPase activity and SNARE complex disassembling rate

Belluzzi, Elisa; Gonnelli, Adriano; Cirnaru, Maria-Daniela; Marte, Antonella; Plotegher, Nicoletta; Russo, Isabella; Civiero, Laura; Cogo, Susanna; Carrion, Maria Perèz; Franchin, Cinzia; Arrigoni, Giorgio; Beltramini, Mariano; Bubacco, Luigi; Onofri, Franco; Piccoli, Giovanni; Greggio, Elisa

doi:10.1186/s13024-015-0066-z

Cited by 149 publications

(173 citation statements)

References 50 publications

Supporting

Mentioning

170

Contrasting

Order By: Relevance

“…To assess whether the DOPAL-induced oligomerization of aS may cause synaptic vesicle damage, we used a pH-sensitive fluorescent protein directly targeted to synaptic vesicles (synaptobrevin2-pHluorin), as a reporter in a total internal reflection fluorescence microscopy (TIRFM) experiment3233 in live cells. Synaptobrevin2-pHluorin fluorescence intensity increases if pH becomes basic, i.e.…”

Section: Resultsmentioning

confidence: 99%

DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

Plotegher

Berti

Ferrari

et al. 2017

Sci Rep

113

150

View full text Add to dashboard Cite

Parkinson’s disease is a neurodegenerative disorder characterized by the death of dopaminergic neurons and by accumulation of alpha-synuclein (aS) aggregates in the surviving neurons. The dopamine catabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is a highly reactive and toxic molecule that leads to aS oligomerization by covalent modifications to lysine residues. Here we show that DOPAL-induced aS oligomer formation in neurons is associated with damage of synaptic vesicles, and with alterations in the synaptic vesicles pools. To investigate the molecular mechanism that leads to synaptic impairment, we first aimed to characterize the biochemical and biophysical properties of the aS-DOPAL oligomers; heterogeneous ensembles of macromolecules able to permeabilise cholesterol-containing lipid membranes. aS-DOPAL oligomers can induce dopamine leak in an in vitro model of synaptic vesicles and in cellular models. The dopamine released, after conversion to DOPAL in the cytoplasm, could trigger a noxious cycle that further fuels the formation of aS-DOPAL oligomers, inducing neurodegeneration.

show abstract

Section: Resultsmentioning

confidence: 99%

DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

Plotegher

Berti

Ferrari

et al. 2017

Sci Rep

113

150

View full text Add to dashboard Cite

show abstract

“…LRRK2 possesses kinase activity in vitro and in cells and many potential substrates have been identified including LRRK2 itself via autophosphorylation largely within the Roc domain (Figure 1) [15,22,23]. LRRK2 substrates include β-tubulin, moesin, FoxO1, Futsch, tau, endophilin A1, RPS15, snapin, NSF, MARK1, RGS2, ArfGAP1, and multiple Rab GTPases [15,24–26]. While most of these substrates are known to be directly phosphorylated by LRRK2 in vitro , it is not yet clear whether they can also be phosphorylated in a cellular context with the notable exception of Rab proteins (i.e.…”

Section: Lrrk2 Structure and Enzymatic Activitymentioning

confidence: 99%

Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

Islam

Moore

2017

Biochemical Society Transactions

View full text Add to dashboard Cite

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson’s disease (PD) with autosomal dominant inheritance. Accordingly, LRRK2 has emerged as a promising therapeutic target for disease modification in PD. Since the first discovery of LRRK2 mutations some 12 years ago, LRRK2 has been the subject of intense investigation. It has been established that LRRK2 can function as a protein kinase, with many putative substrates identified, and can also function as a GTPase that may serve in part to regulate kinase activity. Familial mutations influence both of these enzymatic activities, suggesting that they may be important for the development of PD. Many LRRK2 models have been established to understand the pathogenic effects and mechanisms of familial mutations. Here, we provide a focused discussion of the evidence supporting a role for kinase and GTPase activity in mediating the pathogenic effects of familial LRRK2 mutations in different model systems, with an emphasis on rodent models of PD. We also critically discuss the contribution and relevance of protein aggregation, namely of α-synuclein and tau-proteins, which are known to form aggregates in PD brains harboring LRRK2 mutations, to neurodegeneration in LRRK2 rodent models. We aim to provide a clear and unbiased review of some of the key mechanisms that are important for LRRK2-dependent neurodegeneration in PD.

show abstract

“…G2019S carriers exhibit a phenotype nearly indistinguishable from idiopathic PD, with a late onset and often with LBs pathology [18]. Accumulating evidence indicates that LRRK2 is associated with membrane compartments [19,20] where it phosphorylates key proteins involved in membrane remodeling [17,21,22] and regulates different processes including autophagylysosome pathway [23], vesicular trafficking and protein sorting [14,24]. However, Lrrk2 -/-mice or rats show a normal dopaminergic system, with subtle or no alterations in the number of dopaminergic neurons and in the levels of striatal dopamine [25].…”

Section: Introductionmentioning

confidence: 99%

LRRK2 deficiency impacts ceramide metabolism in brain

Ferrazza

Cogo

Melrose

et al. 2016

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Mutations in LRRK2 gene cause inherited Parkinson's disease (PD) and variations around LRRK2 act as risk factor for disease. Similar to sporadic disease, LRRK2-linked cases show late onset and, typically, the presence of proteinaceous inclusions named Lewy bodies (LBs) in neurons. Recently, defects on ceramide (Cer) metabolism have been recognized in PD. In particular, heterozygous mutations in the gene encoding for glucocerebrosidase (GBA1), a lysosomal enzyme converting glucosyl-ceramides (Glc-Cer) into Cer, increase the risk of developing PD. Although several studies have linked LRRK2 with membrane-related processes and autophagic-lysosomal pathway regulation, whether this protein impinges on the Cer pathway has not been addressed. Here, using a targeted lipidomics approach, we report an altered sphingolipid composition in Lrrk2 -/-mouse brains. In particular, we observe a significant increase of Cer levels in Lrrk2 -/-mice and direct effects on GBA1. Collectively, our results suggest a link between LRRK2 and Cer metabolism, providing new insights into the possible role of this protein in sphingolipids metabolism, with implications for PD therapeutics.

show abstract

LRRK2 phosphorylates pre-synaptic N-ethylmaleimide sensitive fusion (NSF) protein enhancing its ATPase activity and SNARE complex disassembling rate

Cited by 149 publications

References 50 publications

DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function

Mechanisms of LRRK2-dependent neurodegeneration: role of enzymatic activity and protein aggregation

LRRK2 deficiency impacts ceramide metabolism in brain

Contact Info

Product

Resources

About