Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA)

Rademacher, Sebastian; Verheijen, Bert M.; Hensel, Niko; Peters, Miriam; Bora, Gamze; Brandes, Gudrun; Sá, Renata Vieira de; Heidrich, Natascha; Fischer, Silke; Brinkmann, Hella; Pol, W. Ludo van der; Wirth, Brunhilde; Pasterkamp, R. Jeroen; Claus, Peter

doi:10.1093/hmg/ddx282

Cited by 18 publications

(11 citation statements)

References 71 publications

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“…The rod response is mimicked by a specific agonist to the subclass of glutamate receptors responsive to AMPA (α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid) [285]. More mature neurons, 10-14 DIV, utilized both AMPAR and the calcium-permissive NMDA (N-methyl-D-aspartate) receptors for rod induction, which also occurs during a similar time course [286]. SSH1 dephosphorylation by calcineurin may be the mechanism activating cofilin [96].…”

Section: Rods Induced By Excitotoxicitymentioning

confidence: 99%

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Bamburg

Minamide

Wiggan

et al. 2021

Cells

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Proteins of the actin depolymerizing factor (ADF)/cofilin family are ubiquitous among eukaryotes and are essential regulators of actin dynamics and function. Mammalian neurons express cofilin-1 as the major isoform, but ADF and cofilin-2 are also expressed. All isoforms bind preferentially and cooperatively along ADP-subunits in F-actin, affecting the filament helical rotation, and when either alone or when enhanced by other proteins, promotes filament severing and subunit turnover. Although self-regulating cofilin-mediated actin dynamics can drive motility without post-translational regulation, cells utilize many mechanisms to locally control cofilin, including cooperation/competition with other proteins. Newly identified post-translational modifications function with or are independent from the well-established phosphorylation of serine 3 and provide unexplored avenues for isoform specific regulation. Cofilin modulates actin transport and function in the nucleus as well as actin organization associated with mitochondrial fission and mitophagy. Under neuronal stress conditions, cofilin-saturated F-actin fragments can undergo oxidative cross-linking and bundle together to form cofilin-actin rods. Rods form in abundance within neurons around brain ischemic lesions and can be rapidly induced in neurites of most hippocampal and cortical neurons through energy depletion or glutamate-induced excitotoxicity. In ~20% of rodent hippocampal neurons, rods form more slowly in a receptor-mediated process triggered by factors intimately connected to disease-related dementias, e.g., amyloid-β in Alzheimer’s disease. This rod-inducing pathway requires a cellular prion protein, NADPH oxidase, and G-protein coupled receptors, e.g., CXCR4 and CCR5. Here, we will review many aspects of cofilin regulation and its contribution to synaptic loss and pathology of neurodegenerative diseases.

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Section: Rods Induced By Excitotoxicitymentioning

confidence: 99%

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Bamburg

Minamide

Wiggan

et al. 2021

Cells

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“…PlexinD1 is a receptor for class 3 semaphorins and acts as a signalling factor to guide axonal growth. In the Taiwanese mouse model and in iPSC-derived motor neurons from SMA patients, PlexinD1 was shown to be cleaved by metalloproteases, resulting in its functional change from being an attractant to a repellent signalling factor, thereby contributing to growth cone collapse [ 145 ]. In the same study, cleaved PlexinD1 was found to be enriched in actin rods, a pathological structure of elongated actin aggregates also found in some age-related neurodegenerative diseases but not in control cells.…”

Section: Smn and The Cytoskeletonmentioning

confidence: 99%

The role of survival motor neuron protein (SMN) in protein homeostasis

Chaytow

Huang

Gillingwater

et al. 2018

Cell. Mol. Life Sci.

148

115

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Ever since loss of survival motor neuron (SMN) protein was identified as the direct cause of the childhood inherited neurodegenerative disorder spinal muscular atrophy, significant efforts have been made to reveal the molecular functions of this ubiquitously expressed protein. Resulting research demonstrated that SMN plays important roles in multiple fundamental cellular homeostatic pathways, including a well-characterised role in the assembly of the spliceosome and biogenesis of ribonucleoproteins. More recent studies have shown that SMN is also involved in other housekeeping processes, including mRNA trafficking and local translation, cytoskeletal dynamics, endocytosis and autophagy. Moreover, SMN has been shown to influence mitochondria and bioenergetic pathways as well as regulate function of the ubiquitin–proteasome system. In this review, we summarise these diverse functions of SMN, confirming its key role in maintenance of the homeostatic environment of the cell.

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“…Labelling of cofilin-actin rods was performed as described in ref. 22 . Briefly, neurons were rinsed once with KRH-EGTA, fixed 10 min with 4% paraformaldehyde, 4% sucrose in 120 mM sodium phosphate buffer, pH 7.4, supplemented with 2 mM EGTA, and permeabilized with methanol at −20°C for 10 min followed by 20 min in 1% Triton X-100, 4% horse serum (HS) in PBS.…”

Section: Cell Labelling Protocols and Image Acquisitionmentioning

confidence: 99%

Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis

et al. 2020

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Mutations in proline-rich transmembrane protein 2 (PRRT2) have been recently identified as the leading cause of a clinically heterogeneous group of neurological disorders sharing a paroxysmal nature, including paroxysmal kinesigenic dyskinesia and benign familial infantile seizures. To date, studies aimed at understanding its physiological functions in neurons have mainly focused on its ability to regulate neurotransmitter release and neuronal excitability. Here, we show that PRRT2 expression in non-neuronal cell lines inhibits cell motility and focal adhesion turnover, increases cell aggregation propensity, and promotes the protrusion of filopodia, all processes impinging on the actin cytoskeleton. In primary hippocampal neurons, PRRT2 silencing affects the synaptic content of filamentous actin and perturbs actin dynamics. This is accompanied by defects in the density and maturation of dendritic spines. We identified cofilin, an actin-binding protein abundantly expressed at the synaptic level, as the ultimate effector of PRRT2. Indeed, PRRT2 silencing unbalances cofilin activity leading to the formation of cofilin-actin rods along neurites. The expression of a cofilin phospho-mimetic mutant (cof-S3E) is able to rescue PRRT2-dependent defects in synapse density, spine number and morphology, but not the alterations observed in neurotransmitter release. Our data support a novel function of PRRT2 in the regulation of the synaptic actin cytoskeleton and in the formation of synaptic contacts.

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Metalloprotease-mediated cleavage of PlexinD1 and its sequestration to actin rods in the motoneuron disease spinal muscular atrophy (SMA)

Cited by 18 publications

References 71 publications

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

Cofilin and Actin Dynamics: Multiple Modes of Regulation and Their Impacts in Neuronal Development and Degeneration

The role of survival motor neuron protein (SMN) in protein homeostasis

Proline-rich transmembrane protein 2 (PRRT2) regulates the actin cytoskeleton during synaptogenesis

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