Deficiency of the frontotemporal dementia gene GRN results in gangliosidosis

被引：46

作者：

Boland, Sebastian ^{[1
,2
]}

Swarup, Sharan ^{[2
,3
]}

Ambaw, Yohannes A. ^{[1
,2
,4
]}

Malia, Pedro C. ^{[1
,2
]}

Richards, Ruth C. ^{[1
,2
]}

Fischer, Alexander W. ^{[1
,2
]}

Singh, Shubham ^{[1
,2
]}

Aggarwal, Geetika ^{[5
,6
]}

Spina, Salvatore ^{[7
]}

Nana, Alissa L. ^{[7
]}

Grinberg, Lea T. ^{[7
,8
]}

Seeley, William W. ^{[7
,8
]}

Surma, Michal A. ^{[9
]}

Klose, Christian ^{[9
]}

Paulo, Joao A. ^{[2
]}

Nguyen, Andrew D. ^{[5
,6
]}

Harper, J. Wade ^{[2
,3
]}

Walther, Tobias C. ^{[1
,2
,4
,10
,11
]}

Farese, Robert V., Jr. ^{[1
,2
,4
,11
]}

机构：

[1] Harvard TH Chan Sch Publ Hlth, Dept Mol Metab, Boston, MA 02115 USA

[2] Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA

[3] Aligning Sci Parkinsons ASAP Collaborat Res Netwo, Chevy Chase, MD 20815 USA

[4] Harvard TH Chan Sch Publ Hlth, Ctr Causes & Prevent Cardiovasc Dis, Boston, MA 02115 USA

[5] St Louis Univ, Sch Med, Dept Internal Med, Div Geriatr Med, St Louis, MO 63104 USA

[6] St Louis Univ, Sch Med, Dept Physiol & Pharmacol, St Louis, MO 63104 USA

[7] Univ Calif San Francisco, Dept Neurol, Memory & Aging Ctr, San Francisco, CA 94158 USA

[8] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA

[9] LipotypeGmbH, Dresden, Germany

[10] Howard Hughes Med Inst, Boston, MA 02115 USA

[11] Broad Inst Harvard & MIT, Cambridge, MA 02124 USA

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

关键词：

MASS-SPECTROMETRY; LOBAR DEGENERATION; HIGH-THROUGHPUT; HUMAN-BRAIN; MEMBRANE; SYSTEM; MUTATIONS; STRATEGY; LIPIDOME; PLATFORM;

D O I：

10.1038/s41467-022-33500-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Haploinsufficiency of GRN causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), which is cleaved to lysosomal granulin polypeptides. The function of lysosomal granulins and why their absence causes neurodegeneration are unclear. Here we discover that PGRN-deficient human cells and murine brains, as well as human frontal lobes from GRN-mutation FTD patients have increased levels of gangliosides, glycosphingolipids that contain sialic acid. In these cells and tissues, levels of lysosomal enzymes that catabolize gangliosides were normal, but levels of bis(monoacylglycero)phosphates (BMP), lipids required for ganglioside catabolism, were reduced with PGRN deficiency. Our findings indicate that granulins are required to maintain BMP levels to support ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD due to PGRN deficiency and other neurodegenerative diseases.

引用

页数：13

共 52 条

[21] Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic [J].

Logan, Todd ;

Simon, Matthew J. ;

Rana, Anil ;

Cherf, Gerald M. ;

Srivastava, Ankita ;

Davis, Sonnet S. ;

Low, Ray Lieh Yoon ;

Chiu, Chi-Lu ;

Fang, Meng ;

Huang, Fen ;

Bhalla, Akhil ;

Llapashtica, Ceyda ;

Prorok, Rachel ;

Pizzo, Michelle E. ;

Calvert, Meredith E. K. ;

Sun, Elizabeth W. ;

Hsiao-Nakamoto, Jennifer ;

Rajendra, Yashas ;

Lexa, Katrina W. ;

Srivastava, Devendra B. ;

van Lengerich, Bettina ;

Wang, Junhua ;

Robles-Colmenares, Yaneth ;

Kim, Do Jin ;

Duque, Joseph ;

Lenser, Melina ;

Earr, Timothy K. ;

Nguyen, Hoang ;

Chau, Roni ;

Tsogtbaatar, Buyankhishig ;

Ravi, Ritesh ;

Skuja, Lukas L. ;

Solanoy, Hilda ;

Rosen, Howard J. ;

Boeve, Bradley F. ;

Boxer, Adam L. ;

Heuer, Hilary W. ;

Dennis, Mark S. ;

Kariolis, Mihalis S. ;

Monroe, Kathryn M. ;

Przybyla, Laralynne ;

Sanchez, Pascal E. ;

Meisner, Rene ;

Diaz, Dolores ;

Henne, Kirk R. ;

Watts, Ryan J. ;

Henry, Anastasia G. ;

Gunasekaran, Kannan ;

Astarita, Giuseppe ;

Suh, Jung H. .

CELL, 2021, 184 (18) :4651-+

[22] A harmonized classification system for FTLD-TDP pathology [J].

Mackenzie, Ian R. A. ;

Neumann, Manuela ;

Baborie, Atik ;

Sampathu, Deepak M. ;

Du Plessis, Daniel ;

Jaros, Evelyn ;

Perry, Robert H. ;

Trojanowski, John Q. ;

Mann, David M. A. ;

Lee, Virginia M. Y. .

ACTA NEUROPATHOLOGICA, 2011, 122 (01) :111-113

[23] Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update [J].

Mackenzie, Ian R. A. ;

Neumann, Manuela ;

Bigio, Eileen H. ;

Cairns, Nigel J. ;

Alafuzoff, Irina ;

Kril, Jillian ;

Kovacs, Gabor G. ;

Ghetti, Bernardino ;

Halliday, Glenda ;

Holm, Ida E. ;

Ince, Paul G. ;

Kamphorst, Wouter ;

Revesz, Tamas ;

Rozemuller, Annemieke J. M. ;

Kumar-Singh, Samir ;

Akiyama, Haruhiko ;

Baborie, Atik ;

Spina, Salvatore ;

Dickson, Dennis W. ;

Trojanowski, John Q. ;

Mann, David M. A. .

ACTA NEUROPATHOLOGICA, 2010, 119 (01) :1-4

[24] Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury [J].

Martens, Lauren Henl ;

Zhang, Jiasheng ;

Barmada, Sami J. ;

Zhou, Ping ;

Kamiya, Sherry ;

Sun, Binggui ;

Min, Sang-Won ;

Gan, Li ;

Finkbeiner, Steven ;

Huang, Eric J. ;

Farese, Robert V., Jr. .

JOURNAL OF CLINICAL INVESTIGATION, 2012, 122 (11) :3955-3959

[25] Enhancement of TNF-α production by ganglioside GM2 in human mononuclear cell culture [J].

Mizutani, K ;

Oka, N ;

Akiguchi, I ;

Satoi, H ;

Kawasaki, T ;

Kaji, R ;

Kimura, J .

NEUROREPORT, 1999, 10 (04) :703-706

[26] Comprehensive untargeted lipidomic analysis using core-shell C30 particle column and high field orbitrap mass spectrometer [J].

Narvaez-Rivas, Monica ;

Zhang, Qibin .

JOURNAL OF CHROMATOGRAPHY A, 2016, 1440 :123-134

[27] Frontotemporal lobar degeneration - A consensus on clinical diagnostic criteria [J].

Neary, D ;

Snowden, JS ;

Gustafson, L ;

Passant, U ;

Stuss, D ;

Black, S ;

Freedman, M ;

Kertesz, A ;

Robert, PH ;

Albert, M ;

Boone, K ;

Miller, BL ;

Cummings, J ;

Benson, DF .

NEUROLOGY, 1998, 51 (06) :1546-1554

[28] Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay [J].

Nguyen, Andrew D. ;

Nguyen, Thi A. ;

Zhang, Jiasheng ;

Devireddy, Swathi ;

Zhou, Ping ;

Karydas, Anna M. ;

Xu, Xialian ;

Miller, Bruce L. ;

Rigo, Frank ;

Ferguson, Shawn M. ;

Huang, Eric J. ;

Walther, Tobias C. ;

Farese, Robert V., Jr. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (12) :E2849-E2858

[29] Prosaposin is a regulator of progranulin levels and oligomerization [J].

Nicholson, Alexandra M. ;

Finch, NiCole A. ;

Almeida, Marcio ;

Perkerson, Ralph B. ;

van Blitterswijk, Marka ;

Wojtas, Aleksandra ;

Cenik, Basar ;

Rotondo, Sergio ;

Inskeep, Venette ;

Almasy, Laura ;

Dyer, Thomas ;

Peralta, Juan ;

Jun, Goo ;

Wood, Andrew R. ;

Frayling, Timothy M. ;

Fuchsberger, Christian ;

Fowler, Sharon ;

Teslovich, Tanya M. ;

Manning, Alisa K. ;

Kumar, Satish ;

Curran, Joanne ;

Lehman, Donna ;

Abecasis, Goncalo ;

Duggirala, Ravindranath ;

Pottier, Cyril ;

Zahir, Haaris A. ;

Crook, Julia E. ;

Karydas, Anna ;

Mitic, Laura ;

Sun, Ying ;

Dickson, Dennis W. ;

Bu, Guojun ;

Herz, Joachim ;

Yu, Gang ;

Miller, Bruce L. ;

Ferguson, Shawn ;

Petersen, Ronald C. ;

Graff-Radford, Neill ;

Blangero, John ;

Rademakers, Rosa .

NATURE COMMUNICATIONS, 2016, 7

[30]

OBRIEN JS, 1965, J LIPID RES, V6, P537

← 1 2 3 4 5 6 →