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Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss


Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts GM2 to GM3 ganglioside. Hexa−/− mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise GM2 ganglioside via a lysosomal sialidase into glycolipid GA2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4−/−;Hexa−/−) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa−/− or Neu4−/− siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating GM2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa−/− mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa−/− mice.


Vyšlo v časopise: Mice Doubly-Deficient in Lysosomal Hexosaminidase A and Neuraminidase 4 Show Epileptic Crises and Rapid Neuronal Loss. PLoS Genet 6(9): e32767. doi:10.1371/journal.pgen.1001118
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1001118

Souhrn

Tay-Sachs disease is a severe lysosomal disorder caused by mutations in the HexA gene coding for the α-subunit of lysosomal β-hexosaminidase A, which converts GM2 to GM3 ganglioside. Hexa−/− mice, depleted of β-hexosaminidase A, remain asymptomatic to 1 year of age, because they catabolise GM2 ganglioside via a lysosomal sialidase into glycolipid GA2, which is further processed by β-hexosaminidase B to lactosyl-ceramide, thereby bypassing the β-hexosaminidase A defect. Since this bypass is not effective in humans, infantile Tay-Sachs disease is fatal in the first years of life. Previously, we identified a novel ganglioside metabolizing sialidase, Neu4, abundantly expressed in mouse brain neurons. Now we demonstrate that mice with targeted disruption of both Neu4 and Hexa genes (Neu4−/−;Hexa−/−) show epileptic seizures with 40% penetrance correlating with polyspike discharges on the cortical electrodes of the electroencephalogram. Single knockout Hexa−/− or Neu4−/− siblings do not show such symptoms. Further, double-knockout but not single-knockout mice have multiple degenerating neurons in the cortex and hippocampus and multiple layers of cortical neurons accumulating GM2 ganglioside. Together, our data suggest that the Neu4 block exacerbates the disease in Hexa−/− mice, indicating that Neu4 is a modifier gene in the mouse model of Tay-Sachs disease, reducing the disease severity through the metabolic bypass. However, while disease severity in the double mutant is increased, it is not profound suggesting that Neu4 is not the only sialidase contributing to the metabolic bypass in Hexa−/− mice.


Zdroje

1. GravelRA

KabackMM

ProiaRL

SandhoffK

SuzukiK

2001 The GM2 Gangliosidoses.

ScriverCR

BeaudetAL

Sly WS, ValleD

The Metabolic and Molecular Basis of Inherited Disease New York McGraw-Hill 3827 3876

2. MeiklePJ

HopwoodJJ

ClagueAE

CareyWF

1999 Prevalence of lysosomal storage disorders. JAMA 281 249 254

3. KabackMM

RimoinDL

O'BrienJS

1977 Tay-Sachs Disease: Screening and Prevention. New York Alan R. Liss (pub.)

4. AndermannE

ScriverCR

WolfeLS

DanskyL

AndermannF

1977 Genetic variants of Tay-Sachs disease and Sandhoff's disease in French-Canadians, juvenile Tay-Sachs disease in Lebanese Canadians, and a Tay-Sachs screening program in the French-Canadian population.

KabackMM

RimoinDL

O'BrienJS

Tay-Sachs Disease: Screening and Prevention New York Alan R. Liss (pub.) 161 168

5. SangoK

YamanakaS

HoffmannA

OkudaY

GrinbergA

1995 Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat Genet 11 170 176

6. PhaneufD

WakamatsuN

HuangJQ

BorowskiA

PetersonAC

1996 Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases. Hum Mol Genet 5 11 14

7. TaniikeM

YamanakaS

ProiaRL

LangamanC

Bone-TurrentineT

1995 Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease. Acta Neuropath 89 296 304

8. MiklyaevaEI

DongW

BureauA

FattahieR

XuY

2004 Late onset Tay-Sachs disease in mice with targeted disruption of the Hexa gene: behavioral changes and pathology of the central nervous system. Brain Res. 1001 37 50

9. MartinoS

di GirolamoI

CavazzinC

TiribuziR

GalliR

2009 Neural precursor cell cultures from GM2 gangliosidosis animal models recapitulate the biochemical and molecular hallmarks of the brain pathology. J Neurochem 109 135 147

10. SeyrantepeV

CanuelM

ZengJ

LandryK

LiangF

2008 Mice deficient in the Neu4 sialidase exhibit abnormal ganglioside catabolism and lysosomal storage. Hum Mol Genet 17 1556 1568

11. SeyrantepeV

LandryK

TrudelS

HassanJA

MoralesCR

2004 Neu4, a novel human lysosomal lumen sialidase confers normal phenotype to sialidosis cells. J Biol Chem 279 37021 37029

12. ComelliEM

AmadoM

LustigSR

PaulsonJC

2003 Identification and expression of Neu4, a novel murine sialidase. Genetics 321 155 161

13. MontiE

BassiMT

BrescianiR

CiviniS

CrociGL

2004 Molecular cloning and characterization of NEU4, the fourth member of the human sialidase gene family. Genomics 83 445 453

14. YamaguchiK

HataK

KosekiK

ShiozakiK

AkitaH

2005 Evidence for mitochondrial localization of a novel human sialidase (NEU4). Biochem J 390(Pt 1) 85 93

15. IrwinS

1966 Comprehensive observational assessment: A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia (Berl.) 13 222 257

16. NakamuraK

KoikeM

ShitaraK

KuwanaY

KiuragiK

1994 Chimeric anti-ganglioside GM2 antibody with antitumor activity. Cancer Res Mar 15;54 1511 1516

17. HuangJQ

TraslerJM

IgdouraS

MichaudJ

HanalN

1997 Apoptotic cell death in mouse models of GM2 gangliosidosis and observations on human Tay-Sachs and Sandhoff diseases. Hum Mol Genet 6 1879 1885

18. FetissovSO

JacobyAS

BrumovskyPR

ShineJ

IismaaTP

2003 Altered hippocampal expression of neuropeptides in seizure-prone GALR1 knockout mice. Epilepsia 44 1022 1033

19. BiW

YanJ

ShiX

Yuva-PaylorLA

AntalffyBA

2007 Rai1 deficiency in mice causes learning impairment and motor dysfunction, whereas Rai1 heterozygous mice display minimal behavioral phenotypes. Hum Mol Genet 16 1802 1813

20. PshezhetskyAV

AshmarinaM

2001 Lysosomal multienzyme complex: biochemistry, genetics, and molecular pathophysiology. Prog Nucleic Acid Res Mol Biol 69 81 114

21. HiraiwaM

NishizawaM

UdaY

NakajimaT

MiyatakeT

1988 Human placental sialidase: further purification and characterization. J Biochem 103 86 90

22. ManciniGM

HoogeveenAT

GaljaardH

ManssonJE

SvennerholmL

1986 Ganglioside GM1 metabolism in living human fibroblasts with beta-galactosidase deficiency. Hum Genet 73 35 38

23. Ulrich-BottB

KlemB

KaiserR

SprangerJ

CantzM

1987 Lysosomal sialidase deficiency: increased ganglioside content in autopsy tissues of a sialidosis patient. Enzyme 38 262 266

24. HasegawaT

YamaguchiK

WadaT

TakedaA

ItoyamaY

2000 Molecular cloning of mouse ganglioside sialidase and its increased expression in Neuro2a cell differentiation. J Biol Chem 275 8007 8015

25. ZanchettiG

ColombiP

ManzoniM

AnastasiaL

CaimiL

2007 Sialidase NEU3 is a peripheral membrane protein localized on the cell surface and in endosomal structures. Biochem J 408 211 219

26. LemaPP

GirardC

VachonP

2004 Dexamethasone for the treatment of intracerebral hemorrhage using a collagenase-induced cerebral hematoma rat model. J Vet Pharmacol Therap 27 321 328

27. SavardC

LemaPP

HélieP

VachonP

2009 Evaluation of delayed dexamethasone treatment on the outcome of collagenase-induced intracerebral hemorrhage in rats. Comp Med 59 444 448

28. DeipolyiAR

FangS

PalopJJ

YuGQ

WangX

2008 Altered navigational strategy use and visuospatial deficits in hAPP transgenic mice. Neurobiol Aging 29 253 266

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Genetika Reprodukčná medicína

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PLOS Genetics


2010 Číslo 9
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