LRRK2 signaling in neurodegeneration: two decades of progress

Iannotta, Lucia; Greggio, Elisa

doi:10.1042/ebc20210013

Cited by 18 publications

(12 citation statements)

References 161 publications

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“…LRRK2encodes an enzyme with a complicated interaction eventually controlling catalytic GTPase and kinase functions [ 58 ]. This is critical as three LRRK2mutations in the GTPase domain (R1441C, R1441G, and R1441H) and two in the kinase domain (G2019S and I2020T) are linked with an elevated risk of PD.…”

Section: Resultsmentioning

confidence: 99%

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

Bougea

2023

IJMS

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Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are uncommon multifactorial atypical Parkinsonian syndromes, expressed by various clinical features. MSA and PSP are commonly considered sporadic neurodegenerative disorders; however, our understanding is improving of their genetic framework. The purpose of this study was to critically review the genetics of MSA and PSP and their involvement in the pathogenesis. A systemized literature search of PubMed and MEDLINE was performed up to 1 January 2023. Narrative synthesis of the results was undertaken. In total, 43 studies were analyzed. Although familial MSA cases have been reported, the hereditary nature could not be demonstrated. COQ2 mutations were involved in familial and sporadic MSA, without being reproduced in various clinical populations. In terms of the genetics of the cohort, synuclein alpha (SNCA) polymorphisms were correlated with an elevated likelihood of manifesting MSA in Caucasians, but a causal effect relationship could not be demonstrated. Fifteen MAPT mutations were linked with PSP. Leucine-rich repeat kinase 2 (LRRK2) is an infrequent monogenic mutation of PSP. Dynactin subunit 1 (DCTN1) mutations may imitate the PSP phenotype. GWAS have noted many risk loci of PSP (STX6 and EIF2AK3), suggesting pathogenetic mechanisms related to PSP. Despite the limited evidence, it seems that genetics influence the susceptibility to MSA and PSP. MAPT mutations result in the MSA and PSP pathologies. Further studies are crucial to elucidate the pathogeneses of MSA and PSP, which will support efforts to develop novel drug options.

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Section: Resultsmentioning

confidence: 99%

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

Bougea

2023

IJMS

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“…The most frequent mutation (G2019S) located in the kinase domain results in a protein with a gain of kinase activity, associated with increased cellular toxicity 20 . Previous data from our team and other laboratories suggest that LRRK2 sits at the crossroads between cytoskeletal dynamics and vesicular traffic, through interaction with a host of cytoskeletal and vesicle-associated proteins and phosphorylation of a subset of Rab GTPases 23,24 . LRRK2 subcellular localization is dynamically controlled by phosphorylation/dephosphorylation of a cluster of N-terminal serine residues (e.g.…”

Section: Introductionmentioning

confidence: 83%

“…LRRK2 activity seems to be mediated via interactions with a plethora of cytoskeletal and vesicle-associated proteins and via phosphorylation of a subset of Rab GTPases. 14,15 LRRK2 subcellular localization is dynamically controlled by phosphorylation/dephosphorylation of a cluster of N-terminal serine residues (e.g. Ser935 and Ser910), which determines 14-3-3 protein binding.…”

Section: Introductionmentioning

confidence: 99%

LRRK2 regulates synaptic function through BDNF signaling and actin cytoskeleton

Tombesi¹,

Chen²,

Favetta³

et al. 2022

Preprint

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Dendritic spines, small protrusions of the dendrites, constitute the postsynaptic compartment of excitatory synapses. Filamentous actin is the major cytoskeletal constituent of dendritic spines, whose dynamic nature allows them to plastically remodel their shape and volume in response to stimuli. Notably, dendritic spine abnormalities are linked to a number of neurological and neurodegenerative disorders. Here, we show that the Parkinson disease (PD)-associated kinase LRRK2 participates in spine remodeling processing by binding a panel of actin-related proteins enriched in postsynaptic compartments. Phosphorylation of LRRK2 Ser935, which controls LRRK2 subcellular localization, rapidly increases upon brain-derived neurotrophic factor (BDNF) stimulation of differentiated SH-SY5Y cells and primary mouse neurons. Affinity-purification coupled with mass spectrometry (AP-MS/MS) analysis revealed that LRRK2 interactome is significantly reshaped upon BDNF stimulation, with an interconnected network of actin cytoskeleton-associated proteins increasing their binding to LRRK2. Accordingly, Lrrk2 knockout primary neurons exhibit impaired response to BDNF-induced spinogenesis and TrkB signaling. In vivo, one-month old Lrrk2 knockout mice exhibit defects in spine maturation, a phenotype that disappears with age. Finally, by comparing the phosphoproteomes of Lrrk2 wild-type versus Lrrk2 G2019S PD mutant synaptosomes, we found that the differentially phosphorylated proteins are enriched in categories related to postsynaptic structural organization. Taken together, our study discloses a critical function of LRRK2 in shaping dendritic spine morphology during development and defines a mechanistic role of the kinase in postsynaptic actin-cytoskeletal dynamics.

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“…Mutations in Leucine-rich repeat kinase 2 ( LRRK2 ) represent a common cause of familial PD (15). LRRK2 encodes a large multidomain protein equipped with a GTPase Roc-COR domain, a serine-threonine kinase domain and a number of protein-protein interaction domains (16). Mechanistically, LRRK2 mutations increase kinase activity by enhancing LRRK2 substrate phosphorylation through different pathways: pathological mutations localized in the Roc-COR domain (e.g.…”

Section: Introductionmentioning

confidence: 99%

PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner

Iannotta,

Fasiczka,

Favetta

et al. 2024

Preprint

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P21 activated kinase 6 (PAK6) is a serine-threonine kinase with physiological expression enriched in the brain and overexpressed in a number of human tumors. While the role of PAK6 in cancer cells has been extensively investigated, the physiological function of the kinase in the context of brain cells is poorly understood. Our previous work uncovered a link between PAK6 and the Parkinson's disease (PD)-associated kinase LRRK2, with PAK6 controlling LRRK2 activity and subcellular localization via phosphorylation of 14-3-3 proteins. Here, to gain more insights into PAK6 physiological function, we performed protein-protein interaction arrays and identified a subgroup of PAK6 binders related to ciliogenesis. We confirmed that endogenous PAK6 localizes at both the centrosome and the cilium, and positively regulates ciliogenesis not only in tumor cells but also in neurons and astrocytes. Strikingly, PAK6 rescues ciliogenesis and centrosomal cohesion defects associated with the G2019S but not the R1441C LRRK2 PD mutation. Since PAK6 binds LRRK2 via its GTPase/Roc-COR domain and the R1441C mutation is located in the Roc domain, we used microscale thermophoresis and AlphaFold2-based computational analysis to demonstrate that PD mutations in LRRK2 affecting the Roc-COR structure substantially decrease PAK6 affinity, providing a rationale for the differential protective effect of PAK6 toward the distinct forms of mutant LRRK2. Altogether, our study discloses a novel role of PAK6 in ciliogenesis and points to PAK6 as the first LRRK2 modifier with PD mutation-specificity.

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LRRK2 signaling in neurodegeneration: two decades of progress

Cited by 18 publications

References 161 publications

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

LRRK2 regulates synaptic function through BDNF signaling and actin cytoskeleton

PAK6 rescues pathogenic LRRK2-mediated ciliogenesis and centrosomal cohesion defects in a mutation-specific manner

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