Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.
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This work identifies PGRN as an activator of lysosomal cathepsin D activity, and suggests that decreasedCathepsIn D activity due to loss of P GRN contributes to both FTD and NCL pathology in a dose-dependent manner.Abstract:
Frontotemporal dementia (FTD) encompasses a group of neurodegenerative disorders characterized by cognitive and behavioral impairments. Heterozygous mutations in progranulin (PGRN) cause familial FTD and result in decreased PGRN expression, while homozygous mutations result in complete loss of PGRN expression and lead to the neurodegenerative lysosomal storage disorder neuronal ceroid lipofuscinosis (NCL). However, how dose-dependent PGRN mutations contribute to these two different diseases is not well understood. Using iPSC-derived human cortical neurons from FTD patients harboring PGRN mutations, we demonstrate that PGRN mutant neurons exhibit decreased nuclear TDP-43 and increased insoluble TDP-43, as well as enlarged electron-dense vesicles, lipofuscin accumulation, fingerprint-like profiles and granular osmiophilic deposits, suggesting that both FTD and NCL-like pathology are present in PGRN patient neurons as compared to isogenic controls. PGRN mutant neurons also show impaired lysosomal proteolysis and decreased activity of the lysosomal enzyme cathepsin D. Furthermore, we find that PGRN interacts with cathepsin D, and that PGRN increases the activity of cathepsin D but not cathepsins B or L. Finally, we show that granulin E, a cleavage product of PGRN, is sufficient to increase cathepsin D activity. This functional relationship between PGRN and cathepsin D provides a possible explanation for overlapping NCL-like pathology observed in patients with mutations in PGRN or CTSD, the gene encoding cathepsin D. Together, our work identifies PGRN as an activator of lysosomal cathepsin D activity, and suggests that decreased cathepsin D activity due to loss of PGRN contributes to both FTD and NCL pathology in a dose-dependent manner.read more
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Journal ArticleDOI
The lysosomal function of progranulin, a guardian against neurodegeneration
TL;DR: The cellular functions of PGRN, its roles in the nervous system, and its link to multiple neurodegenerative diseases are summarized, with a particular focus dedicated to recent lysosome-related mechanistic developments.
Journal ArticleDOI
Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis.
TL;DR: In vivo support is provided for the efficacy of progranulin-boosting therapies for FTD and NCL due to GRN mutations and several mechanistic questions about the potential of proganulin gene therapy for these disorders are addressed.
Journal ArticleDOI
Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis.
TL;DR: Evidence that lysosomal dysfunction, caused by genetic mutations or toxic-gain of function (i.e. aggregation of TDP-43 or tau), is an important pathogenic disease mechanism in FTD and ALS is summarized.
Journal ArticleDOI
Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.
Todd P. Logan,Matthew Simon,Anil Rana,Gerald M. Cherf,Ankita Srivastava,Sonnet S. Davis,Ray Lieh Yoon Low,Chi-Lu Chiu,Meng Fang,Fen Huang,Akhil Bhalla,Ceyda Llapashtica,Rachel Prorok,Michelle E. Pizzo,Meredith E. K. Calvert,Elizabeth W. Sun,Jennifer Hsiao-Nakamoto,Yashas Rajendra,Katrina W. Lexa,Devendra B. Srivastava,Bettina Van Lengerich,Junhua Wang,Yaneth Robles-Colmenares,Do Jin Kim,Joseph Duque,Melina Lenser,Timothy K. Earr,Hoang Nguyen,Roni Chau,Buyankhishig Tsogtbaatar,Ritesh Ravi,Lukas L. Skuja,Hilda Solanoy,Howard J. Rosen,Bradley F. Boeve,Adam L. Boxer,Hilary W. Heuer,Mark S. Dennis,Mihalis Kariolis,Kathryn M. Monroe,Laralynne Przybyla,Pascal E. Sanchez,René Meisner,Dolores Diaz,Kirk R. Henne,Ryan J. Watts,Anastasia G. Henry,Kannan Gunasekaran,Giuseppe Astarita,Jung H. Suh,Joseph W. Lewcock,Sarah L. DeVos,Gilbert Di Paolo +52 more
TL;DR: In this article, a protein replacement strategy was proposed by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution.
Journal ArticleDOI
Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration.
TL;DR: Therapeutic strategies targeting lysosomes and autophagic machinery have already been tested in several aging-related neurodegenerative diseases with promising results, suggesting that improving lysOSomal function could be similarly beneficial in preserving function in the aging brain.
References
More filters
Journal ArticleDOI
Genome engineering using the CRISPR-Cas9 system
F. Ann Ran,Patrick D. Hsu,Jason Wright,Vineeta Agarwala,Vineeta Agarwala,David A. Scott,Feng Zhang +6 more
TL;DR: A set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies are described.
Journal ArticleDOI
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Journal ArticleDOI
Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.
Katya Rascovsky,John R. Hodges,David S. Knopman,Mario F. Mendez,Joel H. Kramer,John Neuhaus,John C. van Swieten,Harro Seelaar,Elise G.P. Dopper,Chiadi U. Onyike,Argye E. Hillis,Keith A. Josephs,Bradley F. Boeve,Andrew Kertesz,William W. Seeley,Katherine P. Rankin,Julene K. Johnson,Maria Luisa Gorno-Tempini,Howard J. Rosen,Caroline E. Prioleau-Latham,Albert Lee,Christopher M. Kipps,Christopher M. Kipps,Patricia Lillo,Olivier Piguet,Jonathan D. Rohrer,Martin N. Rossor,Jason D. Warren,Nick C. Fox,Douglas Galasko,David P. Salmon,Sandra E. Black,M.-Marsel Mesulam,Sandra Weintraub,Brad C. Dickerson,Janine Diehl-Schmid,Florence Pasquier,Vincent Deramecourt,Florence Lebert,Yolande A.L. Pijnenburg,Tiffany W. Chow,Facundo Manes,Jordan Grafman,Stefano F. Cappa,Morris Freedman,Murray Grossman,Bruce L. Miller +46 more
TL;DR: The revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotmporal lobar degeneration and reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations.
Journal ArticleDOI
TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Tetsuaki Arai,Masato Hasegawa,Haruhiko Akiyama,Kenji Ikeda,Takashi Nonaka,Hiroshi Mori,David M. A. Mann,Kuniaki Tsuchiya,Mari Yoshida,Yoshio Hashizume,Tatsuro Oda +10 more
TL;DR: The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of T DP-43.
Journal ArticleDOI
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Matt Baker,Ian R. A. Mackenzie,Stuart Pickering-Brown,Jennifer Gass,Rosa Rademakers,Caroline Lindholm,Julie S. Snowden,Jennifer Adamson,A. Dessa Sadovnick,Sara Rollinson,Ashley Cannon,Emily Dwosh,David Neary,Stacey Melquist,Anna Richardson,Dennis W. Dickson,Zdenek Berger,Jason L. Eriksen,Todd Robinson,Cynthia Zehr,Chad A. Dickey,Richard Crook,Eileen McGowan,David M. A. Mann,Bradley F. Boeve,Howard Feldman,Mike Hutton +26 more
TL;DR: It is demonstrated that in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles and identified mutations in PGRN as a cause of neurodegenerative disease.
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