Linking Alpha-Synuclein to the Actin Cytoskeleton: Consequences to Neuronal Function

Silva, Marina I. Oliveira da; Liz, Márcia A.

doi:10.3389/fcell.2020.00787

Cited by 34 publications

(26 citation statements)

References 90 publications

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“…α-Synuclein is another protein reported to accumulate within Lewy body in PD and shown to regulate LIMK1 signaling. In culture neurons, α-synuclein activated a signaling cascade resulting in cofilin inactivation, stabilization of actin filaments, and axonal and synaptic integrations through the Rac1-LIMK pathway [180]. In addition, increased cell death and reduced survival of newborn neurons in synuclein transgenic animals may be due to an altered actin cytoskeleton and LIMK1 [171].…”

Section: Limk1 In Parkinson's Diseasementioning

confidence: 99%

LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases

Zablah

Zhang

Gugustea

et al. 2021

Cells

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Learning and memory require structural and functional modifications of synaptic connections, and synaptic deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 and LIMK2) are key regulators of the actin cytoskeleton by affecting the actin-binding protein, cofilin. In addition, LIMK1 is implicated in the regulation of gene expression by interacting with the cAMP-response element-binding protein. Accumulating evidence indicates that LIMKs are critically involved in brain function and dysfunction. In this paper, we will review studies on the roles and underlying mechanisms of LIMKs in the regulation of long-term potentiation (LTP) and depression (LTD), the most extensively studied forms of long-lasting synaptic plasticity widely regarded as cellular mechanisms underlying learning and memory. We will also discuss the involvement of LIMKs in the regulation of the dendritic spine, the structural basis of synaptic plasticity, and memory formation. Finally, we will discuss recent progress on investigations of LIMKs in neurological and mental disorders, including Alzheimer’s, Parkinson’s, Williams–Beuren syndrome, schizophrenia, and autism spectrum disorders.

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Section: Limk1 In Parkinson's Diseasementioning

confidence: 99%

LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases

Zablah

Zhang

Gugustea

et al. 2021

Cells

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“…MAP6 may also indirectly influence the actin cytoskeleton through an effect on signaling cascades as it has been shown to interact with the small GTPase protein Rac2 ( Figure 1 ; Capala et al, 2015 ). Several MAP6 partners have also been shown to interact with actin ( Supplementary Table 1 ), such as spinophilin (Grossman et al, 2004 ) or α-synuclein (Oliveira da Silva and Liz, 2020 ). These interactions support specific actin-related cellular functions for MAP6 and its partners.…”

Section: Map6 Protein Is a Multi-functional Proteinmentioning

confidence: 99%

“…Similarly, α-synuclein, a MAP6 partner ( Figure 1 ), interacts with and nucleates MTs (Cartelli et al, 2016 ). α-synuclein also interacts with actin and reduces F-actin polymerization speed (Sousa et al, 2009 ; Cartelli et al, 2016 ; Oliveira da Silva and Liz, 2020 ). It also participates in signaling cascades and neuroreceptor functions (for review see Emamzadeh, 2016 ; Bernal-Conde et al, 2019 ).…”

Section: Crmps: From Signaling Pathways To Cytoskeleton Functionsmentioning

confidence: 99%

Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories

Cuveillier

Boulan

Ravanello

et al. 2021

Front. Mol. Neurosci.

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The development and function of the central nervous system rely on the microtubule (MT) and actin cytoskeletons and their respective effectors. Although the structural role of the cytoskeleton has long been acknowledged in neuronal morphology and activity, it was recently recognized to play the role of a signaling platform. Following this recognition, research into Microtubule Associated Proteins (MAPs) diversified. Indeed, historically, structural MAPs—including MAP1B, MAP2, Tau, and MAP6 (also known as STOP);—were identified and described as MT-binding and -stabilizing proteins. Extensive data obtained over the last 20 years indicated that these structural MAPs could also contribute to a variety of other molecular roles. Among multi-role MAPs, MAP6 provides a striking example illustrating the diverse molecular and cellular properties of MAPs and showing how their functional versatility contributes to the central nervous system. In this review, in addition to MAP6’s effect on microtubules, we describe its impact on the actin cytoskeleton, on neuroreceptor homeostasis, and its involvement in signaling pathways governing neuron development and maturation. We also discuss its roles in synaptic plasticity, brain connectivity, and cognitive abilities, as well as the potential relationships between the integrated brain functions of MAP6 and its molecular activities. In parallel, the Collapsin Response Mediator Proteins (CRMPs) are presented as examples of how other proteins, not initially identified as MAPs, fall into the broader MAP family. These proteins bind MTs as well as exhibiting molecular and cellular properties very similar to MAP6. Finally, we briefly summarize the multiple similarities between other classical structural MAPs and MAP6 or CRMPs.In summary, this review revisits the molecular properties and the cellular and neuronal roles of the classical MAPs, broadening our definition of what constitutes a MAP.

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“…In this study, we aimed at characterizing mechanisms downstream of αSyn hippocampal pathology underlying synaptic impairment and cognitive dysfunction in Lewy Body dementias. We focused on the actin cytoskeleton, not only due to its critical role in synaptic function, but also because a link between this cell component and αSyn has been increasingly supported by the literature 9, 10 . One of the consequences of the dysregulation of actin dynamics in neurodegenerative disorders is the formation of cofilin-actin rods.…”

Section: Introductionmentioning

confidence: 99%

Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy

Silva

Santejo

Babcock

et al. 2021

Preprint

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Cognitive dysfunction and dementia are presently recognized as major complications in α-synucleinopathies, namely in Dementia with Lewy Bodies (DLB) and Parkinson’s disease with dementia (PDD). In these disorders, α-Synuclein (αSyn) accumulation affects severely the hippocampus by inducing synaptic dysfunction which culminates in cognitive impairment. To characterize the mechanisms underlying αSyn-induced neuronal dysfunction we analysed the effect of overexpression or extracellular administration of αSyn on hippocampal neurons. We observed that αSyn induces the dysregulation of the actin-binding protein cofilin and its assembly into rod structures in a mechanism mediated by the cellular prion protein (PrPC). Moreover, we unraveled cofilin pathology as mediator of αSyn-induced dendritic spine impairment in hippocampal neurons. Importantly, in a synucleinopathy mouse model with cognitive impairment we validated cofilin dysregulation and synaptic dysfunction at the same age when cognitive deficits were observed. Our data supports cofilin as a novel player on hippocampal synaptic dysfunction triggered by αSyn on Lewy Body dementias.

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Linking Alpha-Synuclein to the Actin Cytoskeleton: Consequences to Neuronal Function

Cited by 34 publications

References 90 publications

LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases

LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases

Beyond Neuronal Microtubule Stabilization: MAP6 and CRMPS, Two Converging Stories

Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy

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