Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease

Mutez, Eugénie; Nkiliza, Aurore; Bélarbi, Karim; Broucker, Amélie de; Vanbesien-Mailliot, Christel; Bleuse, S.; Duflot, Aurélie; Comptdaer, Thomas; Semaille, Pierre; Blervaque, Renaud; Hot, David; Leprêtre, Frédéric; Figeac, Martin; Destée, Alain; Chartier-Harlin, Marie-Christine

doi:10.1016/j.nbd.2013.11.007

Cited by 55 publications

(53 citation statements)

References 46 publications

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“…This indicates that the alterations in mTOR and EIF2 signaling represent alterations in neuronal pathways prior to the formation of aggregates in the SN. Moreover, a recent transcriptome study from Mutez and colleagues showed that deregulation of the EIF2 signaling pathway is evident in samples of peripheral blood mononuclear cells of genetic as well as sporadic PD patients compared age-matched healthy controls [52] providing further evidence for a key role of this pathway in both genetic and sporadic forms of PD.…”

Section: Discussionmentioning

confidence: 99%

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

et al. 2015

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Subjects with incidental Lewy body disease (iLBD) may represent the premotor stage of Parkinson’s disease (PD). To elucidate molecular mechanisms underlying neuronal dysfunction and alpha-synuclein pathology in the premotor phase of PD, we investigated the transcriptome of the substantia nigra (SN) of well-characterized iLBD, PD donors and age-matched controls with Braak alpha-synuclein stage ranging from 0–6. In Braak alpha-synuclein stages 1 and 2, we observed deregulation of pathways linked to axonal degeneration, immune response and endocytosis, including axonal guidance signaling, mTOR signaling, EIF2 signaling and clathrin-mediated endocytosis in the SN. In Braak stages 3 and 4, we observed deregulation of pathways involved in protein translation and cell survival, including mTOR and EIF2 signaling. In Braak stages 5 and 6, we observed deregulation of dopaminergic signaling, axonal guidance signaling and thrombin signaling. Throughout the progression of PD pathology, we observed a deregulation of mTOR, EIF2 and regulation of eIF4 and p70S6K signaling in the SN. Our results indicate that molecular mechanisms related to axonal dysfunction, endocytosis and immune response are an early event in PD pathology, whereas mTOR and EIF2 signaling are impaired throughout disease progression. These pathways may hold the key to altering the disease progression in PD.

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Section: Discussionmentioning

confidence: 99%

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

et al. 2015

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“…Pro-inflammatory cytokine levels are elevated in PD subject blood, cerebrospinal fluid, and brain tissue (Collins et al, 2012). Peripheral blood mononuclear cells from PD patients with LRRK2 mutations have changes similar to those seen in mononuclear cells from sporadic PD patients (Mutez et al, 2014). Consequently, a role for LRRK2 has been implicated in microglial pro-inflammatory responses in the brains of PD subjects (Moehle et al, 2012).…”

Section: Lrrk2 and The Immune Systemmentioning

confidence: 94%

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Esteves

Swerdlow

Cardoso

2014

Experimental Neurology

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Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signalling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.

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“…Unbiased transcriptomics techniques to identify disease-specific cellular signatures and signaling pathways modified in disease recently showed a deregulation of pathways related to the translation initiation factor eIF2 in patient peripheral blood mononuclear cells (PBMCs) of both sporadic and genetic PD patients [33]. Of note, repression of translation by eIF2 signaling has been demonstrated in prion disorders and postulated to occur in other prion-like disorders [34].…”

Section: Clinical Observationsmentioning

confidence: 99%

“…Translation factor activity is regulated by cellular signaling processes (reviewed in [47]), such as signaling cascades mediated by phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), or mitogen-activated protein kinases (MAPKs), which modulate activity of general translation factors or factors influencing transport or stability of mRNAs. For example, the mTOR pathway, which responds to growth factors and is deregulated in PD and PD models [33,48], controls several translation proteins such as the eIF4E inhibitor eIF4E binding protein (4E-BP), the kinase of eEF2 or the ribosomal kinase S6K [47][48][49]. In this way, external stimuli such as growth factors or mitogens can affect protein translation activity.…”

Section: Potential Mechanisms Of Protein Translation Deregulation In Pdmentioning

confidence: 99%

Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis

Taymans

Nkiliza

Chartier-Harlin

2015

Trends in Molecular Medicine

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Involvement of the immune system, endocytosis and EIF2 signaling in both genetically determined and sporadic forms of Parkinson's disease

Cited by 55 publications

References 46 publications

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

Evidence for Immune Response, Axonal Dysfunction and Reduced Endocytosis in the Substantia Nigra in Early Stage Parkinson’s Disease

LRRK2, a puzzling protein: Insights into Parkinson's disease pathogenesis

Deregulation of protein translation control, a potential game-changing hypothesis for Parkinson's disease pathogenesis

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