A new case of infantile‐onset hereditary spastic paraplegia with complicated phenotype (<scp>SPG</scp>61) in a consanguineous Russian family

Чухрова, А. Л.; Акимова, И. А.; Щагина, О. А.; Kadnikova, V. A.; Рыжкова, О. П.; Polyakov, A. V.

doi:10.1111/ene.13880

Cited by 6 publications

(4 citation statements)

References 4 publications

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“…1a ). Consistent with the CNS-related phenotypes reported for some patients 8 , 9 , the weight of the brain in Arl6ip1 KO mice was significantly decreased (0.46 g in WT mice compared with 0.39 g in KO mice at 6 months of age; n = 3, unpaired Student’s t -test, P = 0.016). Moreover, cortical neuron (Extended Data Fig.…”

Section: Degeneration Of Neurons In Arl6ip1 Knocko...supporting

confidence: 83%

“…Subsequently, this leads to impaired proteostasis and progressive neurodegeneration. Because ARL6IP1 also binds to FAM134A and FAM134C, two broadly expressed close homologues of FAM134B 2 , which also serve as ER-phagy receptors 26 , this may explain why mutations in ARL6IP1 lead to more severe disease 2 , 3 , 8 , 9 , 27 . In light of the evolutionarily conserved function of FAM134B, the formation of heteromeric clusters of ubiquitinated membrane-shaping proteins to remodel the ER may represent a more general principle of cell homeostasis.…”

Section: Abnormal Er Sheets After Arl6ip1 Disruptionmentioning

confidence: 99%

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Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Foronda

Covarrubias‐Pinto

et al. 2023

Nature

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Membrane-shaping proteins characterized by reticulon homology domains play an important part in the dynamic remodelling of the endoplasmic reticulum (ER). An example of such a protein is FAM134B, which can bind LC3 proteins and mediate the degradation of ER sheets through selective autophagy (ER-phagy)1. Mutations in FAM134B result in a neurodegenerative disorder in humans that mainly affects sensory and autonomic neurons2. Here we report that ARL6IP1, another ER-shaping protein that contains a reticulon homology domain and is associated with sensory loss3, interacts with FAM134B and participates in the formation of heteromeric multi-protein clusters required for ER-phagy. Moreover, ubiquitination of ARL6IP1 promotes this process. Accordingly, disruption of Arl6ip1 in mice causes an expansion of ER sheets in sensory neurons that degenerate over time. Primary cells obtained from Arl6ip1-deficient mice or from patients display incomplete budding of ER membranes and severe impairment of ER-phagy flux. Therefore, we propose that the clustering of ubiquitinated ER-shaping proteins facilitates the dynamic remodelling of the ER during ER-phagy and is important for neuronal maintenance.

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Section: Degeneration Of Neurons In Arl6ip1 Knocko...supporting

confidence: 83%

Section: Abnormal Er Sheets After Arl6ip1 Disruptionmentioning

confidence: 99%

Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Foronda

Covarrubias‐Pinto

et al. 2023

Nature

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“…Missensemutations in the homologous ATL3 can cause autosomal-dominant HSAN1 as well [66][67][68][69] , characterized by delayed wound healing, adult onset painless chronic ulcerations and fractures of the metatarsals, which may result in severe bone destruction. Homozygous loss-of-function mutations in ARL6IP1 can cause a complicated form of HSP with the typical signs of HSAN in terms of pain loss and acromutilations [70][71][72][73][74][75] . Moreover, homozygous loss-of-function mutations in RETREG1 (formerly known as FAM134B) result in HSAN2 76 .…”

Section: [H2] Epigenetics and Transcriptionmentioning

confidence: 99%

Genetic pain loss disorders

Lischka

Laššuthová

Çakar

et al. 2022

Nat Rev Dis Primers

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“…ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1) is an ER-shaping protein, mutations in which cause an autosomal-recessive form of HSP (SPG61) [ 54 , 100 ]. Disease-causing variants identified include frameshift, nonsense and missense mutations, pointing to loss-of-function as the primary mechanism of pathogenicity [ 12 , 17 , 53 , 54 , 90 ]. SPG61 patients exhibit an infant-onset, complicated form of HSP accompanied by distal peripheral neuropathy, although it has recently been suggested that patients carrying homozygous nonsense mutations in ARL6IP1 exhibit a particularly severe form of HSP [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia

Byrne

Garcia-Pardo

Cole

et al. 2022

acta neuropathol commun

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Hereditary spastic paraplegias (HSPs) are a group of inherited, progressive neurodegenerative conditions characterised by prominent lower-limb spasticity and weakness, caused by a length-dependent degeneration of the longest corticospinal upper motor neurons. While more than 80 spastic paraplegia genes (SPGs) have been identified, many cases arise from mutations in genes encoding proteins which generate and maintain tubular endoplasmic reticulum (ER) membrane organisation. The ER-shaping proteins are essential for the health and survival of long motor neurons, however the mechanisms by which mutations in these genes cause the axonopathy observed in HSP have not been elucidated. To further develop our understanding of the ER-shaping proteins, this study outlines the generation of novel in vivo and in vitro models, using CRISPR/Cas9-mediated gene editing to knockout the ER-shaping protein ADP-ribosylation factor-like 6 interacting protein 1 (ARL6IP1), mutations in which give rise to the HSP subtype SPG61. Loss of Arl6IP1 in Drosophila results in progressive locomotor deficits, emulating a key aspect of HSP in patients. ARL6IP1 interacts with ER-shaping proteins and is required for regulating the organisation of ER tubules, particularly within long motor neuron axons. Unexpectedly, we identified physical and functional interactions between ARL6IP1 and the phospholipid transporter oxysterol-binding protein-related protein 8 in both human and Drosophila model systems, pointing to a conserved role for ARL6IP1 in lipid homeostasis. Furthermore, loss of Arl6IP1 from Drosophila neurons results in a cell non-autonomous accumulation of lipid droplets in axonal glia. Importantly, treatment with lipid regulating liver X receptor-agonists blocked lipid droplet accumulation, restored axonal ER organisation, and improved locomotor function in Arl6IP1 knockout Drosophila. Our findings indicate that disrupted lipid homeostasis contributes to neurodegeneration in HSP, identifying a potential novel therapeutic avenue for the treatment of this disorder.

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A new case of infantile‐onset hereditary spastic paraplegia with complicated phenotype (SPG61) in a consanguineous Russian family

Cited by 6 publications

References 4 publications

Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Heteromeric clusters of ubiquitinated ER-shaping proteins drive ER-phagy

Genetic pain loss disorders

Liver X receptor-agonist treatment rescues degeneration in a Drosophila model of hereditary spastic paraplegia

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