Deletion of the Huntingtin Polyglutamine Stretch Enhances Neuronal Autophagy and Longevity in Mice

English version České info

Expansion of a stretch of polyglutamine in huntingtin (htt), the protein product of the IT15 gene, causes Huntington's disease (HD). Previous investigations into the role of the polyglutamine stretch (polyQ) in htt function have suggested that its length may modulate a normal htt function involved in regulating energy homeostasis. Here we show that expression of full-length htt lacking its polyglutamine stretch (ΔQ-htt) in a knockin mouse model for HD (Hdh^140Q/ΔQ), reduces significantly neuropil mutant htt aggregates, ameliorates motor/behavioral deficits, and extends lifespan in comparison to the HD model mice (Hdh^140Q/+). The rescue of HD model phenotypes is accompanied by the normalization of lipofuscin levels in the brain and an increase in the steady-state levels of the mammalian autophagy marker microtubule-associate protein 1 light chain 3-II (LC3-II). We also find that ΔQ-htt expression in vitro increases autophagosome synthesis and stimulates the Atg5-dependent clearance of truncated N-terminal htt aggregates. ΔQ-htt's effect on autophagy most likely represents a gain-of-function, as overexpression of full-length wild-type htt in vitro does not increase autophagosome synthesis. Moreover, Hdh^ΔQ/ΔQ mice live significantly longer than wild-type mice, suggesting that autophagy upregulation may be beneficial both in diseases caused by toxic intracellular aggregate-prone proteins and also as a lifespan extender in normal mammals.

Vyšlo v časopise: Deletion of the Huntingtin Polyglutamine Stretch Enhances Neuronal Autophagy and Longevity in Mice. PLoS Genet 6(2): e32767. doi:10.1371/journal.pgen.1000838
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000838

Souhrn

Zdroje

1. AtwalRS

XiaJ

PinchevD

TaylorJ

EpandRM

2007 Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity. Hum Mol Genet 16 2600 2615

2. FaberPW

BarnesGT

SrinidhiJ

ChenJ

GusellaJF

1998 Huntingtin interacts with a family of WW domain proteins. Hum Mol Genet 7 1463 1474

3. GaoYG

YanXZ

SongAX

ChangYG

GaoXC

2006 Structural Insights into the specific binding of huntingtin proline-rich region with the SH3 and WW domains. Structure 14 1755 1765

4. LiuYF

DethRC

DevysD

1997 SH3 domain-dependent association of huntingtin with epidermal growth factor receptor signaling complexes. J Biol Chem 272 8121 8124

5. The Huntington's Disease Collaborative Research Group 1993 A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72 971 983

6. DiFigliaM

SappE

ChaseKO

DaviesSW

BatesGP

1997 Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277 1990 1993

7. MyersRH

VonsattelJP

StevensTJ

CupplesLA

RichardsonEP

1988 Clinical and neuropathologic assessment of severity in Huntington's disease. Neurology 38 341 347

8. de la MonteSM

VonsattelJP

RichardsonEPJr

1988 Morphometric demonstration of atrophic changes in the cerebral cortex, white matter, and neostriatum in Huntington's disease. J Neuropathol Exp Neurol 47 516 525

9. VonsattelJP

MyersRH

StevensTJ

FerranteRJ

BirdED

1985 Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol 44 559 577

10. CattaneoE

ZuccatoC

TartariM

2005 Normal huntingtin function: an alternative approach to Huntington's disease. Nature Rev Neurosci 6 919 930

11. BaxendaleS

AbdullaS

ElgarG

BuckD

BerksM

1995 Comparative sequence analysis of the human and pufferfish Huntington's disease genes. Nature Genet 10 67 76

12. HarjesP

WankerEE

2003 The hunt for huntingtin function: interaction partners tell many different stories. Trends Biochem Sci 28 425 433

13. KarlovichCA

JohnRM

RamirezL

StainierDY

MyersRM

1998 Characterization of the Huntington's disease (HD) gene homologue in the zebrafish Danio rerio. Gene 217 117 125

14. TartariM

GissiC

Lo SardoV

ZuccatoC

PicardiE

2008 Phylogenetic comparison of huntingtin homologues reveals the appearance of a primitive polyQ in sea urchin. Mol Biol Evol 25 330 338

15. SeongIS

IvanovaE

LeeJM

ChooYS

FossaleE

2005 HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet 14 2871 2880

16. ClaboughEB

ZeitlinSO

2006 Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro. Hum Mol Genet 15 607 623

17. SarkarS

RubinszteinDC

2008 Huntington's disease: degradation of mutant huntingtin by autophagy. FEBS J 275 4263 4270

18. MizushimaN

2007 Autophagy: process and function. Genes Dev 21 2861 2873

19. FilimonenkoM

StuffersS

RaiborgC

YamamotoA

MalerodL

2007 Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J Cell Biol 179 485 500

20. YamamotoA

CremonaML

RothmanJE

2006 Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172 719 731

21. RubinszteinDC

GestwickiJE

MurphyLO

KlionskyDJ

2007 Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6 304 312

22. SarkarS

RavikumarB

FlotoRA

RubinszteinDC

2009 Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies. Cell Death Differ 16 46 56

23. JeongH

ThenF

MeliaTJJr

MazzulliJR

CuiL

2009 Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 137 60 72

24. KabeyaY

MizushimaN

UenoT

YamamotoA

KirisakoT

2000 LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19 5720 5728

25. MenalledLB

SisonJD

DragatsisI

ZeitlinS

ChesseletMF

2003 Time course of early motor and neuropathological anomalies in a knock-in mouse model of Huntington's disease with 140 CAG repeats. J Comp Neurol 465 11 26

26. BarnesCA

1979 Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol 93 74 104

27. KoJ

OuS

PattersonPH

2001 New anti-huntingtin monoclonal antibodies: implications for huntingtin conformation and its binding proteins. Brain Res Bull 56 319 329

28. GoebelHH

HeipertzR

ScholzW

IqbalK

Tellez-NagelI

1978 Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies. Neurology 28 23 31

29. Tellez-NagelI

JohnsonAB

TerryRD

1974 Studies on brain biopsies of patients with Huntington's chorea. J Neuropathol Exp Neurol 33 308 332

30. DaviesSW

TurmaineM

CozensBA

RazaAS

MahalA

1999 From neuronal inclusions to neurodegeneration: neuropathological investigation of a transgenic mouse model of Huntington's disease. Philos Trans R Soc Lond B Biol Sci 354 981 989

31. UchidaK

2006 Lipofuscin-like fluorophores originated from malondialdehyde. Free Radic Res 40 1335 1338

32. GrayDA

WoulfeJ

2005 Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowledge Environ 2005 re1

33. KellerJN

DimayugaE

ChenQ

ThorpeJ

GeeJ

2004 Autophagy, proteasomes, lipofuscin, and oxidative stress in the aging brain. Int J Biochem Cell Biol 36 2376 2391

34. CuervoAM

BergaminiE

BrunkUT

DrogeW

FfrenchM

2005 Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1 131 140

35. GerstbreinB

StamatasG

KolliasN

DriscollM

2005 In vivo spectrofluorimetry reveals endogenous biomarkers that report healthspan and dietary restriction in Caenorhabditis elegans. Aging Cell 4 127 137

36. RubinszteinDC

CuervoAM

RavikumarB

SarkarS

KorolchukV

2009 In search of an “autophagomometer”. Autophagy 5 585 589

37. LiuCL

ChenS

DietrichD

HuBR

2008 Changes in autophagy after traumatic brain injury. J Cereb Blood Flow Metab 28 674 683

38. AtwalRS

TruantR

2008 A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy. Autophagy 4 91 93

39. MizushimaN

YoshimoriT

2007 How to interpret LC3 immunoblotting. Autophagy 3 542 545

40. YamamotoA

TagawaY

YoshimoriT

MoriyamaY

MasakiR

1998 Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct 23 33 42

41. FassE

ShvetsE

DeganiI

HirschbergK

ElazarZ

2006 Microtubules support production of starvation-induced autophagosomes but not their targeting and fusion with lysosomes. J Biol Chem 281 36303 36316

42. SarkarS

RavikumarB

RubinszteinDC

2009 Autophagic clearance of aggregate-prone proteins associated with neurodegeneration. Methods Enzymol 453 83 110

43. KumaA

HatanoM

MatsuiM

YamamotoA

NakayaH

2004 The role of autophagy during the early neonatal starvation period. Nature 432 1032 1036

44. NarainY

WyttenbachA

RankinJ

FurlongRA

RubinszteinDC

1999 A molecular investigation of true dominance in Huntington's disease. J Med Genet 36 739 746

45. SarkarS

PerlsteinEO

ImarisioS

PineauS

CordenierA

2007 Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. Nature Chem Biol 3 331 338

46. RavikumarB

DudenR

RubinszteinDC

2002 Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum Mol Genet 11 1107 1117

47. DuyaoMP

AuerbachAB

RyanA

PersichettiF

BarnesGT

1995 Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269 407 410

48. RavikumarB

VacherC

BergerZ

DaviesJE

LuoS

2004 Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nature Genet 36 585 595

49. CuervoAM

DiceJF

2000 When lysosomes get old. Exp Gerontol 35 119 131

50. HansenM

ChandraA

MiticLL

OnkenB

DriscollM

2008 A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet 4 e24 doi:10.1371/journal.pgen.0040024

51. SimonsenA

CummingRC

BrechA

IsaksonP

SchubertDR

2008 Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4 176 184

52. WangCE

ZhouH

McGuireJR

CerulloV

LeeB

2008 Suppression of neuropil aggregates and neurological symptoms by an intracellular antibody implicates the cytoplasmic toxicity of mutant huntingtin. J Cell Biol 181 803 816

53. TermanA

GustafssonB

BrunkUT

2006 The lysosomal-mitochondrial axis theory of postmitotic aging and cell death. Chem Biol Interact 163 29 37

54. HolzenbergerM

DupontJ

DucosB

LeneuveP

GeloenA

2003 IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421 182 187

55. BluherM

KahnBB

KahnCR

2003 Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299 572 574

56. SelmanC

LingardS

ChoudhuryAI

BatterhamRL

ClaretM

2008 Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J 22 807 818

57. TaguchiA

WartschowLM

WhiteMF

2007 Brain IRS2 signaling coordinates life span and nutrient homeostasis. Science 317 369 372

58. GerlandLM

PeyrolS

LallemandC

BrancheR

MagaudJP

2003 Association of increased autophagic inclusions labeled for beta-galactosidase with fibroblastic aging. Exp Gerontol 38 887 895

59. YoungAR

NaritaM

FerreiraM

KirschnerK

SadaieM

2009 Autophagy mediates the mitotic senescence transition. Genes Dev 23 798 803

60. ChuaKF

MostoslavskyR

LombardDB

PangWW

SaitoS

2005 Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab 2 67 76

61. WilliamsA

SarkarS

CuddonP

TtofiEK

SaikiS

2008 Novel targets for Huntington's disease in an mTOR-independent autophagy pathway. Nature Chem Biol 4 295 305

62. LuoS

VacherC

DaviesJE

RubinszteinDC

2005 Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol 169 647 656

63. BjorkoyG

LamarkT

BrechA

OutzenH

PeranderM

2005 p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol 171 603 614

64. WeissA

KleinC

WoodmanB

SathasivamK

BibelM

2008 Sensitive biochemical aggregate detection reveals aggregation onset before symptom development in cellular and murine models of Huntington's disease. J Neurochem 104 846 858