New hypothesis for the etiology of <i>SPAST‐</i>based hereditary spastic paraplegia

Qiang, Liang; Piermarini, Emanuela; Baas, Peter W.

doi:10.1002/cm.21528

Cited by 17 publications

(14 citation statements)

References 53 publications

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“…Although this conclusion is based on correlation, human patients with SPG4 (spastin encoding gene) develop intellectual disabilities and late-onset dementia. In agreement with a recent hypothesis [48], some microtubule phenotypes observed in our study may be due to a toxic gain-of-function effect of the spastin-K388R mutant (Figs 3, 5 and 6) [48].…”

Section: Plos Biologysupporting

confidence: 93%

Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits

et al. 2020

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Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.

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Section: Plos Biologysupporting

confidence: 93%

Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits

et al. 2020

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“…Some HSPs are due to impaired sphingolipid metabolism, others to defective mitochondrial proteins, and others to gene mutations that code proteins involved in organelle trafficking and shape [34]. One of the latter, spastin, is considered particularly relevant in the disease pathogenesis suggesting that toxic gain-of-function mechanisms operate in a context of a nervous system made vulnerable by haploinsufficiency [121]. A reasonable hypothesis is that any imbalance between the amounts of individual sphingolipids may impair endocytic trafficking, affecting cargo load or autophagy directly, as proven for GBA variants.…”

Section: Discussionmentioning

confidence: 99%

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

Indellicato

Trinchera

2019

IJMS

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Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.

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“…Similarly, MTBd mediates spastin's interaction with tubulin, which is a prerequisite for severing. By contrast, the AAA domain mediates hexamer formation and catalyzes the severing of MTs (3,30,31).…”

Section: Structure and Functions Of Spastinmentioning

confidence: 99%

“…cK2 phosphorylates both kinesin-1 and dynein, which mediate cargo release from the motor (19). A recent review postulated that gain-of-function may be the primary cause of HSP-SPG4 pathogenesis, while haploinsufficiency makes axons more vulnerable to a second insult (31).…”

Section: Role Of Spastin In Hspmentioning

confidence: 99%

Molecular and cellular mechanisms of spastin in neural development and disease (Review)

Liu

Zhang

et al. 2021

Int J Mol Med

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Spastin is a microtubule (MT)-severing enzyme identified from mutations of hereditary spastic paraplegia in 1999 and extensive studies indicate its vital role in various cellular activities. In the past two decades, efforts have been made to understand the underlying molecular mechanisms of how spastin is linked to neural development and disease. Recent studies on spastin have unraveled the mechanistic processes of its MT-severing activity and revealed that spastin acts as an MT amplifier to mediate its remodeling, thus providing valuable insight into the molecular roles of spastin under physiological conditions. In addition, recent research has revealed multiple novel molecular mechanisms of spastin in cellular biological pathways, including endoplasmic reticulum shaping, calcium trafficking, fatty acid trafficking, as well as endosomal fission and trafficking. These processes are closely involved in axonal and dendritic development and maintenance. The current review presents recent biological advances regarding the molecular mechanisms of spastin at the cellular level and provides insight into how it affects neural development and disease.

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New hypothesis for the etiology of SPAST‐based hereditary spastic paraplegia

Cited by 17 publications

References 53 publications

Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits

Spastin depletion increases tubulin polyglutamylation and impairs kinesin-mediated neuronal transport, leading to working and associative memory deficits

The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

Molecular and cellular mechanisms of spastin in neural development and disease (Review)

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