Multiomic elucidation of a coding 99-mer repeat-expansion skeletal muscle disease

Ruggieri, Alessandra; Naumenko, Sergey; Smith, Martin A.; Iannibelli, Eliana; Blasevich, Flavia; Bragato, Cinzia; Gibertini, Sara; Barton, Kirston; Vorgerd, Matthias; Marcus, Katrin; Wang, Peixiang; Maggi, Lorenzo; Mantegazza, Renato; Dowling, James J.; Kley, Rudolf A.; Mora, Marina; Minassian, Berge A.

doi:10.1007/s00401-020-02164-4

Cited by 27 publications

(33 citation statements)

References 11 publications

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“…Targeting to LDs was further increased by the addition of oleic acid to stationary phase cells, which induced large LDs ( Figure 3C ). In addition, we observed some protein at the PM, in particular in the case of Plin4 AH, consistent with observations from human cells and tissues ( Scherer et al, 1998 ; Ruggieri et al, 2020 ). Based on these results, we conclude that the 11-aa repeat regions of Plin1, Plin2, Plin3, and Plin4 are all sufficient for targeting LDs.…”

Section: Resultssupporting

confidence: 91%

“…The sequence of Plin4 is particularly striking in light of a recent study that identified an increased number of homologous repeats (10 additional repeats) in the Plin4 AH encoding region of individuals from a single family with a rare muscular degeneration ( Ruggieri et al, 2020 ). The study proposes that a higher number of repeats in Plin4 leads to protein aggregation in muscle cells, suggesting that the sequence of Plin4 represents a risk for the organism.…”

Section: Discussionmentioning

confidence: 99%

“…Due to its extreme length, Plin4 in particular can cover a large LD surface and could act as a substitute for phospholipids ( Čopič et al, 2018 ). A recent study has identified expansion of Plin4 33-aa repeats in a family with a rare autosomal-dominant progressive myopathy, underscoring the importance of studying this protein ( Ruggieri et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Giménez-Andrés

Emeršič

Antoine-Bally

et al. 2021

eLife

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Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain the targeting of perilipins, the most abundant and specific amphipathic proteins of LDs, which are weakly hydrophobic. A striking example is Plin4, whose gigantic and repetitive AH lacks bulky hydrophobic residues. Using a range of complementary approaches, we show that Plin4 forms a remarkably immobile and stable protein layer at the surface of cellular or in vitro generated oil droplets, and decreases LD size. Plin4 AH stability on LDs is exquisitely sensitive to the nature and distribution of its polar residues. These results suggest that Plin4 forms stable arrangements of adjacent AHs via polar/electrostatic interactions, reminiscent of the organization of apolipoproteins in lipoprotein particles, thus pointing to a general mechanism of AH stabilization via lateral interactions.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Giménez-Andrés

Emeršič

Antoine-Bally

et al. 2021

eLife

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show abstract

“…Targeting to LDs was further increased by the addition of oleic acid to stationary phase cells, which induced large LDs (Figure 3C). In addition, we observed some protein at the PM, in particular in the case of longer Plin4 AHs, consistent with observations from human cells and tissues (Scherer et al, 1998; Ruggieri et al, 2020). Based on these results, we conclude that the 11-aa repeat regions of Plin1, Plin2, Plin3, and Plin4 are all sufficient for targeting LDs.…”

Section: Resultssupporting

confidence: 91%

“…Due to its extreme length, Plin4 in particular can cover a large LD surface and could act as a substitute for phospholipids (Copic et al, 2018). A recent study has identified expansion of Plin4 33-aa repeats in a family with a rare autosomal dominant progressive myopathy, underscoring the importance of studying this protein (Ruggieri et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Giménez-Andrés

Emeršič

Antoine-Bally

et al. 2020

Preprint

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Numerous proteins target lipid droplets (LDs) through amphipathic helices (AHs). It is generally assumed that AHs insert bulky hydrophobic residues in packing defects at the LD surface. However, this model does not explain the targeting of perilipins, the most abundant and specific amphipathic proteins of LDs. The gigantic Plin4 contains a highly repetitive AH that lacks bulky hydrophobic residues, and its LD targeting depends strongly on its length. We show that Plin4 forms a remarkably immobile protein layer at the surface of cellular or artificial LDs, making them stable over days. This Plin4 AH feature is not shared with the AHs of other perilipins, which display much faster dynamics on lipid surfaces. Plin4 AH stability on LDs is exquisitely sensitive to the nature and distribution of its polar residues. These results suggest that Plin4 forms stable arrangements of adjacent AHs via polar interactions.

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Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

et al. 2022

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he presentation of primary hypotonia in the neonatal intensive care unit (NICU) is complex to diagnose. Although our understanding of the genetic basis of hypotonia has advanced significantly in the past decade, 1-5 there remains a lag in implementation of state-of-the-art genetic testing along with variation in diagnostic approaches across institutions. Availability of effective treatments for genetic conditions, such as congenital myasthenic syndromes or spinal muscular atrophy (SMA), [6][7][8] highlights the importance of a timely diagnosis, and therapies for other hypotonic conditions will probably become available in the future. Therefore, prompt genetic diagnosis is increasingly informing clinical care decision and benefit from targeted treatments. [9][10][11][12] Here, we have developed a consensus approach to genetic testing for infants with unexplained hypotonia. Experts volunteered from 5 medical centers that are members of the International Precision Child HealthPartnership(IPCHiP):RoyalChildren'sHospital,Melbourne,

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Multiomic elucidation of a coding 99-mer repeat-expansion skeletal muscle disease

Cited by 27 publications

References 11 publications

Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Exceptional stability of a perilipin on lipid droplets depends on its polar residues, suggesting multimeric assembly

Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review

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