First patient with hereditary spastic paraplegia type 8 in Poland

Bogucki, Piotr; Sobczyńska-Tomaszewska, Agnieszka

doi:10.1002/ccr3.1080

Cited by 5 publications

(4 citation statements)

References 7 publications

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“…This progressive neurodegenerative disorder is clinically characterised by central motor system deficits leading to spastic paraparesis of the lower limbs ( Fink, 2013 ). Until now, 11 point mutations and one exonic deletion in the strumpellin gene have been reported to cause SPG8 ( Bogucki and Sobczyńska-Tomaszewska, 2017 ). Of the 11 disease-causing point mutations, eight, including the N471D mutation, which was the subject of our investigation, are localised in the central spectrin-like repeats ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Based on predicted secondary structure elements, strumpellin can be divided into three parts: an N-terminal part, from amino acid 1 to 240; a central part, from residue 241 to 791, with five spectrin-like repeats; and a C-terminal part. Until now, 11 strumpellin point mutations and one exonic deletion have been identified in a total of 16 families, of which most cause a pure motor form of HSP ( Bogucki and Sobczyńska-Tomaszewska, 2017 ; Jahic et al, 2014 ; Valdmanis et al, 2007 ). An additional strumpellin splice site mutation has been identified as the cause of a form of the Ritscher–Schinzel syndrome ( Elliott et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Expression of N471D strumpellin leads to defects in the endolysosomal system

Lin

Rijal

Karow

et al. 2018

Disease Models &Amp; Mechanisms

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Hereditary spastic paraplegias (HSPs) are genetically diverse and clinically characterised by lower limb weakness and spasticity. The N471D and several other point mutations of human strumpellin (Str; also known as WASHC5), a member of the Wiskott–Aldrich syndrome protein and SCAR homologue (WASH) complex, have been shown to cause a form of HSP known as spastic paraplegia 8 (SPG8). To investigate the molecular functions of wild-type (WT) and N417D Str, we generated Dictyostelium Str− cells and ectopically expressed StrWT-GFP or StrN471D-GFP in Str− and WT cells. Overexpression of both proteins apparently caused a defect in cell division, as we observed a clear increase in multinucleate cells. Real-time PCR analyses revealed no transcriptional changes in WASH complex subunits in Str− cells, but western blots showed a twofold decrease in the SWIP subunit. GFP-trap experiments in conjunction with mass-spectrometric analysis revealed many previously known, as well as new, Str-interacting proteins, and also proteins that no longer bind to StrN471D. At the cellular level, Str− cells displayed defects in cell growth, phagocytosis, macropinocytosis, exocytosis and lysosomal function. Expression of StrWT-GFP in Str− cells rescued all observed defects. In contrast, expression of StrN471D-GFP could not rescue lysosome morphology and exocytosis of indigestible material. Our results underscore a key role for the WASH complex and its core subunit, Str, in the endolysosomal system, and highlight the fundamental importance of the Str N471 residue for maintaining lysosome morphology and dynamics. Our data indicate that the SPG8-causing N471D mutation leads to a partial loss of Str function in the endolysosomal system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of N471D strumpellin leads to defects in the endolysosomal system

Lin

Rijal

Karow

et al. 2018

Disease Models &Amp; Mechanisms

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“…Further biochemical evidence will be needed to clarify the organization, definition and functional role of COMMander. p.N471D [107] p.R583S [108] p.S591P [109] p.L619F [107] p.V620A [110,111] p.V626F [107] p.G696A [112] p.E713K [113] g.ex11-15del [108] c.3335+2T>A…”

Section: Boxmentioning

confidence: 99%

Endosomal Retrieval of Cargo: Retromer Is Not Alone

McNally

Cullen

2018

Trends in Cell Biology

132

143

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Endosomes are major protein sorting stations in cells. Endosomally localised multi-protein complexes sort integral proteins, including signaling receptors, nutrient transporters, adhesion molecules, and lysosomal hydrolase receptors, for lysosomal degradation or conversely for retrieval and subsequent recycling to various membrane compartments. Correct endosomal sorting of these proteins is essential for maintaining cellular homeostasis, with defects in endosomal sorting implicated in various human pathologies including neurodegenerative disorders. Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. While retromer is a major player in endosomal retrieval and recycling, several studies have recently identified retrieval mechanisms that are independent of retromer. Here, we review endosomal retrieval complexes, with a focus on recently discovered retromer-independent mechanisms.

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“…Ritscher-Schinzel syndrome is a developmental multi-organ disease with craniofacial, cerebellar and cardiac abnormalities [4,8]. To date, 18 different SPG8-causing mutations have been reported comprising 16 missense mutations, a single frameshift mutation, and one multi-exonic deletion mutation [1,2,[9][10][11][12][13][14][15]; the genetic basis of Ritscher-Schinzel syndrome 1 is a homozygous splice site mutation [3,4]. An autopsy of a 70-yearold female SPG8 patient harbouring the heterozygous p.V626F mutation revealed a severe atrophy of the thoracic spinal cord in conjunction with demyelination and loss of neurons in this region [16].…”

Section: Introductionmentioning

confidence: 99%

N471D WASH complex subunit strumpellin knock‐in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue

Clemen

Schmidt

Winter

et al. 2021

Neuropathology Appl Neurobio

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Aims: We investigated N471D WASH complex subunit strumpellin (Washc5) knock-in and Washc5 knock-out mice as models for hereditary spastic paraplegia type 8 (SPG8).Methods: We generated heterozygous and homozygous N471D Washc5 knock-in mice and subjected them to a comprehensive clinical, morphological and laboratory parameter screen, and gait analyses. Brain tissue was used for proteomic analysis. Furthermore, we generated heterozygous Washc5 knock-out mice. WASH complex subunit strumpellin expression was determined by qPCR and immunoblotting.Results: Homozygous N471D Washc5 knock-in mice showed mild dilated cardiomyopathy, decreased acoustic startle reactivity, thinner eye lenses, increased alkaline A full list of consortium members and their affiliations is provided in the Appendix A.

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First patient with hereditary spastic paraplegia type 8 in Poland

Cited by 5 publications

References 7 publications

Expression of N471D strumpellin leads to defects in the endolysosomal system

Expression of N471D strumpellin leads to defects in the endolysosomal system

Endosomal Retrieval of Cargo: Retromer Is Not Alone

N471D WASH complex subunit strumpellin knock‐in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue

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