Cross-talk between LRRK2 and PKA: implication for Parkinson's disease?

Greggio, Elisa; Bubacco, Luigi; Russo, Isabella

doi:10.1042/bst20160396

Cited by 31 publications

(25 citation statements)

References 51 publications

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“…Such trafficking could be altered due to differential phosphorylation of Rab8a (Steger et al, 2016 ) or NSF (Belluzzi et al, 2016 ), both of which are involved in AMPA subunit trafficking (Nishimune et al, 1998 ; Gerges et al, 2004 ). As mentioned previously, LRRK2 binds to, and negatively regulates, PKA (Parisiadou et al, 2014 ), which also modulates receptor insertion and cytoskeleton dynamics (see Greggio et al, 2017 ). The R1441C/G mutation disrupts the interaction between LRRK2 and PKA, causing aberrant phosphorylation of downstream proteins (Muda et al, 2014 ; Parisiadou et al, 2014 ).…”

Section: Molecular Interactors and The Loci Of Lrrk2 Dysfunctionmentioning

confidence: 74%

“…Neither of these residues are predicted LRRK2 phosphorylation sites; thus, the reduction suggests impaired activity of another kinase, or increased activity of a phosphatase, conferred by the G2019S mutation. A potential candidate is protein kinase A (PKA), which potentiates SV recycling via phosphorylation of synapsin-I on S9 (Cesca et al, 2010 ) and may be negatively regulated by LRRK2 (Parisiadou et al, 2014 ; Greggio et al, 2017 ). In contrast to reduced phosphorylation of Ser603 and Ser9 residues (Beccano-Kelly et al, 2014 ), phosphorylation of the putative LRRK2 substrate residues Thr337 and Thr339 is increased in cortical neurons expressing hG2019S-LRRK2 (Marte et al, 2019 ).…”

Section: Molecular Interactors and The Loci Of Lrrk2 Dysfunctionmentioning

confidence: 99%

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A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2

Kuhlmann

Milnerwood

2020

Front. Mol. Neurosci.

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Since the discovery of LRRK2 mutations causal to Parkinson’s disease (PD) in the early 2000s, the LRRK2 protein has been implicated in a plethora of cellular processes in which pathogenesis could occur, yet its physiological function remains elusive. The development of genetic models of LRRK2 PD has helped identify the etiological and pathophysiological underpinnings of the disease, and may identify early points of intervention. An important role for LRRK2 in synaptic function has emerged in recent years, which links LRRK2 to other genetic forms of PD, most notably those caused by mutations in the synaptic protein α-synuclein. This point of convergence may provide useful clues as to what drives dysfunction in the basal ganglia circuitry and eventual death of substantia nigra (SN) neurons. Here, we discuss the evolution and current state of the literature placing LRRK2 at the synapse, through the lens of knock-out, overexpression, and knock-in animal models. We hope that a deeper understanding of LRRK2 neurobiology, at the synapse and beyond, will aid the eventual development of neuroprotective interventions for PD, and the advancement of useful treatments in the interim.

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Section: Molecular Interactors and The Loci Of Lrrk2 Dysfunctionmentioning

confidence: 74%

Section: Molecular Interactors and The Loci Of Lrrk2 Dysfunctionmentioning

confidence: 99%

A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2

Kuhlmann

Milnerwood

2020

Front. Mol. Neurosci.

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“…Malfunction of LRRK2 is correlated to PD pathogenesis suggesting that LRRK2 activity needs to be tightly controlled (Martin et al, 2014). Upstream and downstream regulators of LRRK2 have been described including kinases (e.g., PKA, casein kinase 1α), phosphatases (e.g., protein phosphatase 1), and small G-proteins (e.g., Rab29) (Lobbestael et al, 2013;Chia et al, 2014;Greggio et al, 2017;Purlyte et al, 2018). Proteins of the highly conserved 14-3-3 family represent another class of interaction partners providing control on a cellular level.…”

Section: Discussionmentioning

confidence: 99%

Binding of the Human 14-3-3 Isoforms to Distinct Sites in the Leucine-Rich Repeat Kinase 2

et al. 2020

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Proteins of the 14-3-3 family are well known modulators of the leucine-rich repeat kinase 2 (LRRK2) regulating kinase activity, cellular localization, and ubiquitylation. Although binding between those proteins has been investigated, a comparative study of all human 14-3-3 isoforms interacting with LRRK2 is lacking so far. In a comprehensive approach, we quantitatively analyzed the interaction between the seven human 14-3-3 isoforms and LRRK2-derived peptides covering both, reported and putative 14-3-3 binding sites. We observed that phosphorylation is an absolute prerequisite for 14-3-3 binding and generated binding patterns of 14-3-3 isoforms to interact with peptides derived from the N-terminal phosphorylation cluster (S910 and S935), the Roc domain (S1444) and the C-terminus. The tested 14-3-3 binding sites in LRRK2 preferentially were recognized by the isoforms γ and η, whereas the isoforms and especially σ showed the weakest or no binding. Interestingly, the possible pathogenic mutation Q930R in LRRK2 drastically increases binding affinity to a peptide encompassing pS935. We then identified the autophosphorylation site T2524 as a so far not described 14-3-3 binding site at the very C-terminus of LRRK2. Binding affinities of all seven 14-3-3 isoforms were quantified for all three binding regions with pS1444 displaying the highest affinity of all measured singly phosphorylated peptides. The strongest binding was detected for the combined phosphosites S910 and S935, suggesting that avidity effects are important for high affinity interaction between 14-3-3 proteins and LRRK2.

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“…Accumulating evidence indicates a functional interaction between LRRK2 and PKA, although the precise molecular mechanisms of this cross-talk still need to be elucidated [ 31 ]. In this study, using in vitro and ex vivo systems with hyperactive or inactive LRRK2 and different readouts of PKA signaling, we validated LRRK2 kinase activity as the negative regulator of PKA activation.…”

Section: Discussionmentioning

confidence: 99%

“…The available literature supports the notion that the functional interaction between LRRK2 and PKA may be bidirectional. PKA can act upstream of LRRK2 through direct phosphorylation of distinct LRRK2 serine residues [ 20 , 32 ], but also LRRK2 can operate upstream of PKA and negatively regulate its activity [ 17 , 19 ] with apparent different mechanisms in neurons and microglia [ 31 ]. Neuronal LRRK2 was suggested to act as an AKAP by tethering PKA signaling at specific subcellular domains independent of its kinase activity [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Leucine-rich repeat kinase 2 controls protein kinase A activation state through phosphodiesterase 4

Russo

Benedetto

Kaganovich

et al. 2018

J Neuroinflammation

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BackgroundEvidence indicates a cross-regulation between two kinases, leucine-rich repeat kinase 2 (LRRK2) and protein kinase A (PKA). In neurons, LRRK2 negatively regulates PKA activity in spiny projecting neurons during synaptogenesis and in response to dopamine D1 receptor activation acting as an A-anchoring kinase protein (AKAP). In microglia cells, we showed that LRRK2 kinase activity negatively regulates PKA, impacting NF-κB p50 signaling and the inflammatory response. Here, we explore the molecular mechanism underlying the functional interaction between LRRK2 and PKA in microglia.MethodsTo understand which step of PKA signaling is modulated by LRRK2, we used a combination of in vitro and ex vivo systems with hyperactive or inactive LRRK2 as well as different readouts of PKA signaling.ResultsWe confirmed that LRRK2 kinase activity acts as a negative regulator of PKA activation state in microglia. Specifically, we found that LRRK2 controls PKA by affecting phosphodiesterase 4 (PDE4) activity, modulating cAMP degradation, content, and its dependent signaling. Moreover, we showed that LRRK2 carrying the G2019S pathological mutation downregulates PKA activation causing a reduction of PKA-mediated NF-κB inhibitory signaling, which results, in turn, in increased inflammation in LRRK2 G2019S primary microglia upon α-synuclein pre-formed fibrils priming.ConclusionsOverall, our findings indicate that LRRK2 kinase activity is a key regulator of PKA signaling and suggest PDE4 as a putative LRRK2 effector in microglia. In addition, our observations suggest that LRRK2 G2019S may favor the transition of microglia toward an overactive state, which could widely contribute to the progression of the pathology in LRRK2-related PD.

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Cross-talk between LRRK2 and PKA: implication for Parkinson's disease?

Cited by 31 publications

References 51 publications

A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2

A Critical LRRK at the Synapse? The Neurobiological Function and Pathophysiological Dysfunction of LRRK2

Binding of the Human 14-3-3 Isoforms to Distinct Sites in the Leucine-Rich Repeat Kinase 2

Leucine-rich repeat kinase 2 controls protein kinase A activation state through phosphodiesterase 4

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