Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration

Mutations in >50 genes, including spastin and atlastin, lead to hereditary spastic paraplegia (HSP). We previously demonstrated that reduction of spastin leads to a deficit in axon regeneration in a Drosophila model. Axon regeneration was similarly impaired in neurons when HSP proteins atlastin, seipin, and spichthyin were reduced. Impaired regeneration was dependent on genetic background and was observed when partial reduction of HSP proteins was combined with expression of dominant-negative microtubule regulators, suggesting that HSP proteins work with microtubules to promote regeneration. Microtubule rearrangements triggered by axon injury were, however, normal in all genotypes. We examined other markers to identify additional changes associated with regeneration. Whereas mitochondria, endosomes, and ribosomes did not exhibit dramatic repatterning during regeneration, the endoplasmic reticulum (ER) was frequently concentrated near the tip of the growing axon. In atlastin RNAi and spastin mutant animals, ER accumulation near single growing axon tips was impaired. ER tip concentration was observed only during axon regeneration and not during dendrite regeneration. In addition, dendrite regeneration was unaffected by reduction of spastin or atlastin. We propose that the HSP proteins spastin and atlastin promote axon regeneration by coordinating concentration of the ER and microtubules at the growing axon tip.

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Loss of the Mitochondrial Fission GTPase Drp1 Contributes to Neurodegeneration in a Drosophila Model of Hereditary Spastic Paraplegia

Brain Sciences ◽

10.3390/brainsci10090646 ◽

2020 ◽

Vol 10 (9) ◽

pp. 646

Author(s):

Philippa C. Fowler ◽

Dwayne J. Byrne ◽

Craig Blackstone ◽

Niamh C. O'Sullivan

Keyword(s):

Hereditary Spastic Paraplegia ◽

Neurodegenerative Disorder ◽

Mitochondrial Fission ◽

Dominant Negative ◽

In Vivo Model ◽

Mitochondrial Morphology ◽

Autophagic Flux ◽

Spastic Paraplegia ◽

Drosophila Model

Mitochondrial morphology, distribution and function are maintained by the opposing forces of mitochondrial fission and fusion, the perturbation of which gives rise to several neurodegenerative disorders. The large guanosine triphosphate (GTP)ase dynamin-related protein 1 (Drp1) is a critical regulator of mitochondrial fission by mediating membrane scission, often at points of mitochondrial constriction at endoplasmic reticulum (ER)-mitochondrial contacts. Hereditary spastic paraplegia (HSP) subtype SPG61 is a rare neurodegenerative disorder caused by mutations in the ER-shaping protein Arl6IP1. We have previously reported defects in both the ER and mitochondrial networks in a Drosophila model of SPG61. In this study, we report that knockdown of Arl6IP1 lowers Drp1 protein levels, resulting in reduced ER–mitochondrial contacts and impaired mitochondrial load at the distal ends of long motor neurons. Increasing mitochondrial fission, by overexpression of wild-type Drp1 but not a dominant negative Drp1, increases ER–mitochondrial contacts, restores mitochondrial load within axons and partially rescues locomotor deficits. Arl6IP1 knockdown Drosophila also demonstrate impaired autophagic flux and an accumulation of ubiquitinated proteins, which occur independent of Drp1-mediated mitochondrial fission defects. Together, these findings provide evidence that impaired mitochondrial fission contributes to neurodegeneration in this in vivo model of HSP.

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Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

eLife ◽

10.7554/elife.23882 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 25

Author(s):

Belgin Yalçın ◽

Lu Zhao ◽

Martin Stofanko ◽

Niamh C O'Sullivan ◽

Zi Han Kang ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Hereditary Spastic Paraplegia ◽

Membrane Curvature ◽

Degenerative Disease ◽

Ultrastructural Analysis ◽

Motor Axons ◽

Spastic Paraplegia ◽

Partial Loss ◽

And Function ◽

Tubular Endoplasmic Reticulum

Axons contain a smooth tubular endoplasmic reticulum (ER) network that is thought to be continuous with ER throughout the neuron; the mechanisms that form this axonal network are unknown. Mutations affecting reticulon or REEP proteins, with intramembrane hairpin domains that model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). We show that Drosophila axons have a dynamic axonal ER network, which these proteins help to model. Loss of HSP hairpin proteins causes ER sheet expansion, partial loss of ER from distal motor axons, and occasional discontinuities in axonal ER. Ultrastructural analysis reveals an extensive ER network in axons, which shows larger and fewer tubules in larvae that lack reticulon and REEP proteins, consistent with loss of membrane curvature. Therefore HSP hairpin-containing proteins are required for shaping and continuity of axonal ER, thus suggesting roles for ER modeling in axon maintenance and function.

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Hereditary spastic paraplegia associated with a rare endoplasmic reticulum lipid raft-associated protein 2 mutation

International Journal of Contemporary Pediatrics ◽

10.18203/2349-3291.ijcp20204055 ◽

2020 ◽

Vol 7 (10) ◽

pp. 2077

Author(s):

Sai Chandar Dudipala ◽

Naveen Reddy Cheruku ◽

Krishna Chaithanya Battu

Keyword(s):

Endoplasmic Reticulum ◽

Cerebral Palsy ◽

Lipid Raft ◽

Hereditary Spastic Paraplegia ◽

Autosomal Recessive ◽

Adult Population ◽

Complex Form ◽

Spastic Paraplegia ◽

Childhood Onset ◽

Exonic Deletion

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. It can present as pure form or complex form. It can be present from infancy to adulthood, but majority in adult population. Childhood onset HSP must be differentiated from common conditions like cerebral palsy, neurodegenerative disorders and metabolic disorders. Many patients with pediatric HSP are mistakenly diagnosed with cerebral palsy. In children with spastic paraplegia in whom no acquired cause identified, HSP should be considered. Here we diagnosed a 6-year-old boy with HSP who presented with progressive spastic paraplegia, intellectual disability, seizures, joint contractures and cataract. His genetic study revealed exonic deletion of endoplasmic reticulum lipid raft-associated protein gene, which is associated with complicated Autosomal recessive HSP 18 (SPG18). HSP 18 was rarely described in literature.

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Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia

Nature Communications ◽

10.1038/s41467-019-12620-9 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 5

Author(s):

Matias Wagner ◽

Daniel P. S. Osborn ◽

Ina Gehweiler ◽

Maike Nagel ◽

Ulrike Ulmer ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Hereditary Spastic Paraplegia ◽

Degradation Pathway ◽

Therapeutic Interventions ◽

Spastic Paraplegia ◽

Ubiquitin E3 Ligase ◽

Wide Range ◽

Inositol 1,4,5 Trisphosphate ◽

Cerebellar Ataxias ◽

Trisphosphate Receptor

Abstract Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.

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