XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome

Park, Jae-Sook; Neiman, Aaron M.

doi:10.1091/mbc.e19-08-0439-t

Cited by 48 publications

(87 citation statements)

References 31 publications

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“…Signal for Calnexin was also found in the lighter fractions but had a wider distribution (fractions 1-10) than the PM marker Na + /K + ATPase. The protein XK, which has been implicated in non-Huntington's chorea (Park and Neiman, 2020), distributes to light fractions 1-5 and to the center of the gradient (fractions 7-9). Syntaxin 6, a marker of trans-golgi network (TGN) and TGN-derived light vesicles distributes to fractions 1-4 and dense fractions 14-16 in Q7/Q7 mice.…”

Section: Analysis Of Optiprep Fractions Of Q7/q7 and Q175/q7 Hd Striamentioning

confidence: 99%

Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

Iuliano

Seeley

Sapp

et al. 2021

Front. Synaptic Neurosci.

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Dysfunction at synapses is thought to be an early change contributing to cognitive, psychiatric and motor disturbances in Huntington’s disease (HD). In neurons, mutant Huntingtin collects in aggregates and distributes to the same sites as wild-type Huntingtin including on membranes and in synapses. In this study, we investigated the biochemical integrity of synapses in HD mouse striatum. We performed subcellular fractionation of striatal tissue from 2 and 6-month old knock-in Q175/Q7 HD and Q7/Q7 mice. Compared to striata of Q7/Q7 mice, proteins including GLUT3, Na+/K+ ATPase, NMDAR 2b, PSD95, and VGLUT1 had altered distribution in Q175/Q7 HD striata of 6-month old mice but not 2-month old mice. These proteins are found on plasma membranes and pre- and postsynaptic membranes supporting hypotheses that functional changes at synapses contribute to cognitive and behavioral symptoms of HD. Lipidomic analysis of mouse fractions indicated that compared to those of wild-type, fractions 1 and 2 of 6 months Q175/Q7 HD had altered levels of two species of PIP2, a phospholipid involved in synaptic signaling, increased levels of cholesterol ester and decreased cardiolipin species. At 2 months, increased levels of species of acylcarnitine, phosphatidic acid and sphingomyelin were measured. EM analysis showed that the contents of fractions 1 and 2 of Q7/Q7 and Q175/Q7 HD striata had a mix of isolated synaptic vesicles, vesicle filled axon terminals singly or in clusters, and ER and endosome-like membranes. However, those of Q175/Q7 striata contained significantly fewer and larger clumps of particles compared to those of Q7/Q7. Human HD postmortem putamen showed differences from control putamen in subcellular distribution of two proteins (Calnexin and GLUT3). Our biochemical, lipidomic and EM analysis show that the presence of the HD mutation conferred age dependent disruption of localization of synaptic proteins and lipids important for synaptic function. Our data demonstrate concrete biochemical changes suggesting altered integrity of synaptic compartments in HD mice that may mirror changes in HD patients and presage cognitive and psychiatric changes that occur in premanifest HD.

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Section: Analysis Of Optiprep Fractions Of Q7/q7 and Q175/q7 Hd Striamentioning

confidence: 99%

Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

Iuliano

Seeley

Sapp

et al. 2021

Front. Synaptic Neurosci.

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“…While there is growing evidence that members of the VPS13 protein family are involved in the non-vesicular transport of phospholipids [ 16 , 17 , 18 , 19 ], the precise function of these proteins in humans remains incompletely understood. It is most likely that impaired lipid transfer, and consequently, disturbed organelle lipid homeostasis, contributes to neuronal dysfunction in this disease [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease

Peikert

Glaß

Federti

et al. 2021

JPM

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Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the VPS13A gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target. Methods: We evaluated an individual off-label treatment with the tyrosine kinase inhibitor dasatinib (100 mg/d, 25.8–50.4 weeks) of three ChAc patients. Alongside thorough safety monitoring, we assessed motor and non-motor scales (e.g., MDS-UPDRS, UHDRS, quality of life) as well as routine and experimental laboratory parameters (e.g., serum neurofilament, Lyn kinase activity, actin cytoskeleton in red blood cells). Results: Dasatinib appeared to be reasonably safe. The clinical parameters remained stable without significant improvement or deterioration. Regain of deep tendon reflexes was observed in one patient. Creatine kinase, serum neurofilament levels, and acanthocyte count did not reveal consistent effects. However, a reduction of initially elevated Lyn kinase activity and accumulated autophagy markers, as well as a partial restoration of the actin cytoskeleton, was found in red blood cells. Conclusions: We report on the first treatment approach with disease-modifying intention in ChAc. The experimental parameters indicate target engagement in red blood cells, while clinical effects on the central nervous system could not be proven within a rather short treatment time. Limited knowledge on the natural history of ChAc and the lack of appropriate biomarkers remain major barriers for “clinical trial readiness”. We suggest a panel of outcome parameters for future clinical trials in ChAc.

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“…Studies of mammalian VPS13A and VPS13C have demonstrated that they not only are localized at membrane contact sites, but also tether adjacent membranes (Kumar et al, 2018). Moreover, studies of the mammalian VPS13 protein family have shown paralogue-specific localizations (Seifert et al, 2011;Kumar et al, 2018;Yeshaw et al, 2019;Park and Neiman, 2020). VPS13A populates ER-mitochondria contacts, where it may have taken over some of the functions of ERMES, VPS13C is localized at ER-late endosomes/lysosome contacts (Kumar et al, 2018) and VPS13B resides predominantly in the Golgi complex region (Seifert et al, 2011).…”

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confidence: 99%

VPS13D bridges the ER to Miro containing membranes

Guillén-Samander

Leonzino

Hanna

et al. 2020

Preprint

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Mitochondria, which are excluded from the secretory pathway, depend on lipid transport proteins for their lipid supply from the ER, where most lipids are synthesized. In yeast, the outer membrane GTPase Gem1 is an accessory factor of ERMES, an ER-mitochondria tethering complex that contains lipid transport domains and plays a function, partially redundant with VPS13, in lipid transfer between the two organelles. In metazoa, where VPS13, but not ERMES, is present, the Gem1 orthologue Miro has been linked to mitochondrial motility but not to lipid transport. Here we show that Miro recruits to mitochondria the lipid transport protein VPS13D which, like Miro, is an essential protein in mammals, and whose localization had remained elusive. We also show that VPS13D can tether mitochondria to the ER in a Miro- and VAP-dependent way. These findings reveal a so far missing link between function(s) of Gem1/Miro in yeast and higher eukaryotes, where Miro is a Parkin substrate, with potential implications for Parkinson’s disease pathogenesis.SummaryProtein-mediated ER-mitochondria lipid transfer is critical for eukaryotic cells. However, the underlying machinery is not well conserved. Guillén-Samander et al, show that Gem1/Miro is an evolutionary conserved link between the yeast ERMES complex and the mammalian lipid transfer protein VPS13D.

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XK is a partner for VPS13A: a molecular link between Chorea-Acanthocytosis and McLeod Syndrome

Cited by 48 publications

References 31 publications

Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

Disposition of Proteins and Lipids in Synaptic Membrane Compartments Is Altered in Q175/Q7 Huntington’s Disease Mouse Striatum

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease

VPS13D bridges the ER to Miro containing membranes

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