颗粒蛋白前体在神经系统疾病中的研究进展

doi:10.3969/j.issn.1673-5765.2019.07.016

摘要/Abstract

摘要：

颗粒蛋白前体（progranulin，PGRN）是一种多功能的分泌型糖蛋白。其表达水平及相关基因的异常改变与神经系统炎性病变、退行性病变、变性疾病、脑中溶酶体的稳态及血脑屏障完整性密切相关，参与到多种神经系统疾病的病理过程。本文对PGRN的生物学作用及其与相关神经系统疾病的研究进展进行综述，以期为相关患者的干预及相关疾病的研究提供思路及理论依据。

文章导读： 颗粒蛋白前体对多种神经系统疾病的诊治有着重要意义，本文综述了颗粒蛋白前体与多种神经系统疾病的关系及相关研究现况。

关键词: 颗粒蛋白前体; 神经系统疾病; 脑梗死; 血脑屏障; 炎症

Abstract:

Progranulin (PGRN) is a multifunctional secretory glycoprotein. The abnormality in PGRN expression and related genes are closely related to nervous system inflammatory lesions, degenerative diseases, neurodegenerative diseases, brain cell lysosome homeostasis and bloodbrain barrier integrity, and PGRN is involved in various pathological processes in such diseases. This article reviewed the biological effects of PGRN and progress in the role of PGRN in some neurological diseases, to provide ideas and theoretical basis for research and treatment in some neurological diseases.

Key words: Progranulin; Neurological disease; Cerebral infarction; Blood-brain barrier;Inflammation

张青，张蓓，李亚军. 颗粒蛋白前体在神经系统疾病中的研究进展[J]. 中国卒中杂志, 2019, 14(07): 733-739.

ZHANG Qing, ZHANG Bei, LI Ya-Jun. Progress of Role of Progranulin in Nervous System Diseases[J]. Chinese Journal of Stroke, 2019, 14(07): 733-739.

参考文献

[1] LIU C J，BOSCH X. Progranulin：a growth factor，a

novel TNFR ligand and a drug target[J]. Pharmacol

Ther，2012，133（1）：124-132.

[2] YANG D，WANG L L，DONG T T，et al.

Progranulin promotes colorectal cancer proliferation

and angiogenesis through TNFR2/Akt and ERK

signaling pathways[J]. Am J Cancer Res，2015，5

（10）：3085-3097.

[3] KANAZAWA M，KAWAMURA K，TAKAHASHI

T，et al. Multiple therapeutic effects of progranulin

on experimental acute ischaemic stroke[J]. Brain，

2015，138（7）：1932-1948.

[4] XU J，XILOURI M，BRUBAN J，et al. Extracellular

progranulin protects cortical neurons from toxic

insults by activating survival signaling[J/OL].

Neurobiol Aging，2011，32（12）：2326.e5-e16. https：

//doi.org/10.1016/j.neurobiolaging.2011.06.017.

[5] FU W，HU W，SHI L，et al. Foxo4- and Stat3-

dependent IL-10 production by progranulin in

regulatory T cells restrains inflammatory arthritis[J].

FASEB J，2016，31（4）：1354-1367.

[6] YIN F，BANERJEE R，THOMAS B，et al.

Exaggerated inflammation，impaired host defense，

and neuropathology in progranulin-deficient mice[J].

J Exp Med，2010，207（1）：117-128.

[7] HAN Y，SI M，ZHAO Y，et al. Progranulin Protects

against osteonecrosis of the femoral head by

activating ERK1/2 pathway[J]. Inflammation，2017，

40（3）：946-955.

[8] SUGIHARA H，MIYAJI K，YAMANOUCHI

K，et al. Progranulin deficiency leads to prolonged

persistence of macrophages，accompanied with

myofiber hypertrophy in regenerating muscle[J]. J

Vet Med Sci，2018，80（2）：346-353.

[9] MENZEL L，KLEBER L，FRIEDRICH C，et al.

Progranulin protects against exaggerated axonal

injury and astrogliosis following traumatic brain

injury[J]. Glia，2017，65（2）：278-292.

[10] TAO J，JI F，WANG F，et al. Neuroprotective

effects of progranulin in ischemic mice[J/OL]. Brain

Res，2012，1436：130-136. https：//doi.org/10.1016/

j.brainres.2011.11.063.

[11] EGASHIRA Y，SUZUKI Y，AZUMA Y，et al. The

growth factor progranulin attenuates neuronal injury

induced by cerebral ischemia-reperfusion through

the suppression of neutrophil recruitment[J/OL]. J

Neuroinflammation，2013，10：105. https：//doi.

org/10.1186/1742-2094-10-105.

[12] VAN DAMME P，VAN HOECKE A，

LAMBRECHTS D，et al. Progranulin functions as

a neurotrophic factor to regulate neurite outgrowth

and enhance neuronal survival[J]. J Cell Biol，2008，

181（1）：37-41.

[13] GASS J，LEE W C，COOK C，et al. Progranulin

regulates neuronal outgrowth independent of

sortilin[J/OL]. Mol Neurodegener，2012，7：33. https：

//doi.org/10.1186/1750-1326-7-33.

[14] CHITRAMUTHU B P，KAY D G，BATEMAN A，

et al. Neurotrophic effects of progranulin in vivo in

reversing motor neuron defects caused by over or

under expression of TDP-43 or FUS[J/OL]. PloS One，

2017，12（3）：e0174784. https：//doi.org/10.1371/

journal.pone.0174784.

[15] KANAZAWA M，TAKAHASHI T，NISHIZAWA M，

et al. Therapeutic strategies to attenuate hemorrhagic

transformation after tissue plasminogen activator

treatment for acute ischemic stroke[J]. J Atheroscler

Thromb，2017，24（3）：240-253.

[16] SHU Q，FAN H，LI S J，et al. Protective effects

of Progranulin against focal cerebral ischemiareperfusion

injury in rats by suppressing

endoplasmic reticulum stress and NF-kappaB

activation in reactive astrocytes[J]. J Cell Biochem，

2018，119（8）：6584-6597.

[17] JACKMAN K，KAHLES T，LANE D，et al.

Progranulin deficiency promotes post-ischemic

blood-brain barrier disruption[J]. J Neurosci，2013，

33（50）：19 579-19 589.

[18] XIE S，LU L，LIU L，et al. Progranulin and shortterm

outcome in patients with acute ischaemic

stroke[J]. Eur J Neurol，2016，23（3）：648-655.

[19] FUJITA K，CHEN X，HOMMA H，et al. Targeting

Tyro3 ameliorates a model of PGRN-mutant FTLDTDP

via tau-mediated synaptic pathology[J]. Nat

Commun，2018，9（1）：433.

[20] MAO Q，WANG D，LI Y，et al. Disease and

region specificity of granulin immunopositivities

in Alzheimer disease and frontotemporal lobar

degeneration[J]. J Neuropathol Exp Neurol，2017，76

（11）：957-968. [21] ANTONELL A，GIL S，SÁNCHEZ-VALLE R，

et al. Serum progranulin levels in patients with

frontotemporal lobar degeneration and Alzheimer's

disease：detection of GRN mutations in a Spanish

cohort[J]. J Alzheimers Dis，2012，31（3）：581-591.

[22] PAUSHTER D H，DU H，FENG T，et al. The

lysosomal function of progranulin，a guardian

against neurodegeneration[J]. Acta Neuropathol，

2018，136（1）：1-17.

[23] HOLLER C J，TAYLOR G，DENG Q，et al.

Intracellular proteolysis of progranulin generates

stable，lysosomal granulins that are haploinsufficient

in patients with frontotemporal dementia caused by

GRN mutations[J]. eNeuro，2017，4（4）：100-117.

[24] EVERS B M，RODRIGUEZNAVAS C，TESLA

R J，et al. Lipidomic and Transcriptomic basis of

lysosomal dysfunction in progranulin deficiency[J].

Cell Rep，2017，20（11）：2565-2574.

[25] MINAMI S S，MIN S W，KRABBE G，et al.

Progranulin protects against amyloid β deposition

and toxicity in Alzheimer's disease mouse models[J].

Nat Med，2014，20（10）：1157-1164.

[26] TAKAHASHI H，KLEIN Z A，BHAGAT S M，et

al. Opposing effects of progranulin deficiency on

amyloid and tau pathologies via microglial TYROBP

network[J]. Acta Neuropathol，2017，133（5）：785-

807.

[27] HOSOKAWA M，TANAKA Y，ARAI T，et al.

Progranulin haploinsufficiency reduces amyloid beta

deposition in Alzheimer's disease model mice[J].

Exp Anim，2018，67（1）：63-70.

[28] VAN KAMPEN J M，KAY D G. Progranulin

gene delivery reduces plaque burden and synaptic

atrophy in a mouse model of Alzheimer's disease[J/

OL]. PloS One，2017，12（8）：e0182896. https：//doi.

org/10.1371/journal.pone.0182896.

[29] WIDER C，FOROUD T，WSZOLEK Z K. Clinical

implications of gene discovery in Parkinson's disease

and parkinsonism[J]. Movement Disorders，2010，25

（Suppl 1）：S15-S20.

[30] VAN KAMPEN J M，BARANOWSKI D，KAY D

G. Progranulin gene delivery protects dopaminergic

neurons in a mouse model of Parkinson’s disease[J/

OL]. PloS One，2014，9（5）：e97032. https：//doi.

org/10.1371/journal.pone.0097032.

[31] ROVELET-LECRUX A，DERAMECOURT V，

LEGALLIC S，et al. Deletion of the progranulin gene

in patients with frontotemporal lobar degeneration

or Parkinson disease[J]. Neurobiol Dis，2008，31（1）：

41-45.

[32] JIAN J，LI G，HETTINGHOUSE A，et al.

Progranulin：a key player in autoimmune diseases[J/

OL]. Cytokine，2018，101：48-55. https：//doi.

org/10.1016/j.cyto.2016.08.007.

[33] VERCELLINO M，FENOGLIO C，GALIMBERTI

D，et al. Progranulin genetic polymorphisms

influence progression of disability and relapse

recovery in multiple sclerosis[J]. Mult Scler，2016，

22（8）：1007-1012.

[34] VERCELLINO M，GRIFONI S，ROMAGNOLO

A，et al. Progranulin expression in brain tissue and

cerebrospinal fluid levels in multiple sclerosis[J].

Mult Scler，2011，17（10）：1194-1201.

[35] FENOGLIO C，SCALABRINI D，ESPOSITO F，et

al. Progranulin gene variability increases the risk for

primary progressive multiple sclerosis in males[J].

Genes Immun，2010，11（6）：497-503.