Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease

Fil, Daniel; DeLoach, Abigail; Yadav, Shilpi; Alkam, Duah; MacNicol, Melanie C.; Singh, Awantika; Compadre, César M.; Goellner, Joseph J.; O’Brien, Charles A.; Fahmi, Tariq; Basnakian, Alexei G.; Calingasan, Noel Y.; Klessner, Jodi L.; Béal, F; Peters, Owen M.; Metterville, Jake; Brown, Robert H.; Ling, Karen; Rigo, Frank; Özdinler, P. Hande; Kiaei, Mahmoud

doi:10.1093/hmg/ddw429

Cited by 57 publications

(119 citation statements)

References 69 publications

(57 reference statements)

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“…4a), they dragged their feet during end-stage, and displayed gait and walking problems (Fig. 4b), similar to previously reported ALS mouse models [18, 25, 64, 74, 75]. To further assess the timing and the extent of their motor function defects, changes in rotarod (Fig.…”

Section: Resultssupporting

confidence: 80%

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as “TDP-43 pathology” in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown. In an effort to define the underlying causes of corticospinal motor neuron (CSMN) degeneration, we generated and characterized a novel CSMN reporter line with TDP-43 pathology, the prp-TDP-43A315T-UeGFP mice. We find that TDP-43 pathology related intracellular problems emerge very early in the disease. The Betz cells in humans and CSMN in mice both have impaired mitochondria, and display nuclear membrane and ER defects with respect to TDP-43 pathology.

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Section: Resultssupporting

confidence: 80%

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

et al. 2018

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“…Similar to our profilin2a mutant S129D, the profilin1 G118V displayed a marked decrease in G‐actin binding . Interestingly, mice harboring the G118V profilin1 mutation developed an ALS‐like pathophysiology with a tendency for an altered F/G‐actin ratio before disease onset becoming significant at onset and late‐symptomatic stages . This demonstrates the importance of profilin‐linked actin dynamics for the pathology of motoneuron‐diseases.…”

Section: Discussionsupporting

confidence: 74%

Profilin2a‐phosphorylation as a regulatory mechanism for actin dynamics

et al. 2019

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Profilin is a major regulator of actin dynamics in multiple specific processes localized in different cellular compartments. This specificity is not only meditated by its binding to actin but also its interaction with phospholipids such as phosphatidylinositol (4,5)‐bisphosphate (PIP2) at the membrane and a plethora of proteins containing poly‐L‐proline (PLP) stretches. These interactions are fine‐tuned by posttranslational modifications such as phosphorylation. Several phospho‐sites have already been identified for profilin1, the ubiquitously expressed isoform. However, little is known about the phosphorylation of profilin2a. Profilin2a is a neuronal isoform important for synapse function. Here, we identified several putative profilin2a phospho‐sites in silico and tested recombinant phospho‐mimetics with regard to their actin‐, PLP‐, and PIP2‐binding properties. Moreover, we assessed their impact on actin dynamics employing a pyrene‐actin polymerization assay. Results indicate that distinct phospho‐sites modulate specific profilin2a functions. We could identify a molecular switch site at serine residue 71 which completely abrogated actin binding—as well as other sites important for fine‐tuning of different functions, for example, tyrosine 29 for PLP binding. Our findings suggest that differential profilin2a phosphorylation is a sensitive mechanism for regulating its neuronal functions. Moreover, the dysregulation of profilin2a phosphorylation may contribute to neurodegeneration.

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“…Eight mutations in PFN1 were found to be associated with fALS 1–5 . All of the PFN1 mutations, except E117G, are specific to a subset of fALS patients 6–8 , as are the SOD1 and TDP-43 mutations.…”

Section: Introductionmentioning

confidence: 99%

ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation

Kiaei

Balasubramaniam

Kumar

et al. 2018

Sci Rep

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Profilin-1 (PFN1) is a 140-amino-acid protein with two distinct binding sites―one for actin and one for poly-L-proline (PLP). The best-described function of PFN1 is to catalyze actin elongation and polymerization. Thus far, eight DNA mutations in the PFN1 gene encoding the PFN1 protein are associated with human amyotrophic lateral sclerosis (ALS). We and others recently showed that two of these mutations (Gly118Val or G118V and Cys71Gly or C71G) cause ALS in rodents. In vitro studies suggested that Met114Thr and Thr109Met cause the protein to behave abnormally and cause neurotoxicity. The mechanism by which a single amino acid change in human PFN1 causes the degeneration of motor neurons is not known. In this study, we investigated the structural perturbations of PFN1 caused by each ALS-associated mutation. We used molecular dynamics simulations to assess how these mutations alter the secondary and tertiary structures of human PFN1. Herein, we present our in silico data and analysis on the effect of G118V and T109M mutations on PFN1 and its interactions with actin and PLP. The substitution of valine for glycine reduces the conformational flexibility of the loop region between the α-helix and β-strand and enhances the hydrophobicity of the region. Our in silico analysis of T109M indicates that this mutation alters the shape of the PLP-binding site and reduces the flexibility of this site. Simulation studies of PFN1 in its wild type (WT) and mutant forms (both G118V and T109M mutants) revealed differential fluctuation patterns and the formation of salt bridges and hydrogen bonds between critical residues that may shed light on differences between WT and mutant PFN1. In particular, we hypothesize that the flexibility of the actin- and PLP-binding sites in WT PFN1 may allow the protein to adopt slightly different conformations in its free and bound forms. These findings provide new insights into how each of these mutations in PFN1 might increase its propensity for misfolding and aggregation, leading to its dysfunction.

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Mutant Profilin1 transgenic mice recapitulate cardinal features of motor neuron disease

Cited by 57 publications

References 69 publications

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology

Profilin2a‐phosphorylation as a regulatory mechanism for actin dynamics

ALS-causing mutations in profilin-1 alter its conformational dynamics: A computational approach to explain propensity for aggregation

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