. 2017 Mar 29;9(383):eaai7866.

doi: 10.1126/scitranslmed.aai7866.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Tania F Gendron^{1

2}, Jeannie Chew^{1

2}, Jeannette N Stankowski¹, Lindsey R Hayes³, Yong-Jie Zhang^{1

2}, Mercedes Prudencio^{1

2}, Yari Carlomagno¹, Lillian M Daughrity¹, Karen Jansen-West¹, Emilie A Perkerson¹, Aliesha O'Raw¹, Casey Cook^{1

2}, Luc Pregent¹, Veronique Belzil¹, Marka van Blitterswijk^{1

2}, Lilia J Tabassian¹, Chris W Lee^{1

2}, Mei Yue¹, Jimei Tong¹, Yuping Song¹, Monica Castanedes-Casey¹, Linda Rousseau¹, Virginia Phillips¹, Dennis W Dickson^{1

2}, Rosa Rademakers^{1

2}, John D Fryer^{1

2}, Beth K Rush⁴, Otto Pedraza⁴, Ana M Caputo⁵, Pamela Desaro⁵, Carla Palmucci⁵, Amelia Robertson⁵, Michael G Heckman⁶, Nancy N Diehl⁶, Edythe Wiggs⁷, Michael Tierney⁷, Laura Braun⁷, Jennifer Farren⁷, David Lacomis⁸, Shafeeq Ladha⁹, Christina N Fournier¹⁰, Leo F McCluskey¹¹, Lauren B Elman¹¹, Jon B Toledo^{12

13}, Jennifer D McBride¹³, Cinzia Tiloca¹⁴, Claudia Morelli¹⁴, Barbara Poletti¹⁴, Federica Solca¹⁴, Alessandro Prelle¹⁵, Joanne Wuu¹⁶, Jennifer Jockel-Balsarotti¹⁷, Frank Rigo¹⁸, Christine Ambrose¹⁹, Abhishek Datta²⁰, Weixing Yang²⁰, Denitza Raitcheva²¹, Giovanna Antognetti²², Alexander McCampbell²³, John C Van Swieten²⁴, Bruce L Miller²⁵, Adam L Boxer²⁵, Robert H Brown²⁶, Robert Bowser⁹, Timothy M Miller¹⁷, John Q Trojanowski¹³, Murray Grossman¹¹, James D Berry²⁷, William T Hu¹⁰, Antonia Ratti^{14

28}, Bryan J Traynor²⁹, Matthew D Disney³⁰, Michael Benatar¹⁶, Vincenzo Silani^{14

28}, Jonathan D Glass^{10

31}, Mary Kay Floeter⁷, Jeffrey D Rothstein³, Kevin B Boylan⁵, Leonard Petrucelli^{32

2}

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
² Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁶ Section of Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA.
⁷ Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Departments of Neurology and Pathology, University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
⁹ Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
¹⁰ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹¹ Department of Neurology and the Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Department of Neurology, Houston Methodist Neurological Institute, Houston, TX 77030, USA.
¹³ Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁵ Department of Neurology and Stroke Unit, Ospedale Maggiore di Crema, Crema, Italy.
¹⁶ Department of Neurology, University of Miami, Miami, FL 33136, USA.
¹⁷ Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁸ Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
¹⁹ Aleta Biotherapeutics, Natick, MA 01760, USA.
²⁰ Protein Chemistry, Biogen Idec, Cambridge, MA 02142, USA.
²¹ Global Biomarker and Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA.
²² Biologics Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA.
²³ Neurology Research, Biogen Idec, Cambridge, MA 02142, USA.
²⁴ Department of Neurology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands.
²⁵ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
²⁶ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
²⁷ Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁸ Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy.
²⁹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA.
³⁰ Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
³¹ Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
³² Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. petrucelli.leonard@mayo.edu.

PMID: 28356511
PMCID: PMC5576451
DOI: 10.1126/scitranslmed.aai7866

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Tania F Gendron et al. Sci Transl Med. 2017.

. 2017 Mar 29;9(383):eaai7866.

doi: 10.1126/scitranslmed.aai7866.

Authors

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
² Mayo Graduate School, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore, MD 21205, USA.
⁴ Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁵ Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA.
⁶ Section of Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA.
⁷ Motor Neuron Disorders Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Departments of Neurology and Pathology, University of Pittsburgh School of Medicine and the University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
⁹ Departments of Neurology and Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA.
¹⁰ Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
¹¹ Department of Neurology and the Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Department of Neurology, Houston Methodist Neurological Institute, Houston, TX 77030, USA.
¹³ Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
¹⁴ Department of Neurology-Stroke Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁵ Department of Neurology and Stroke Unit, Ospedale Maggiore di Crema, Crema, Italy.
¹⁶ Department of Neurology, University of Miami, Miami, FL 33136, USA.
¹⁷ Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
¹⁸ Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
¹⁹ Aleta Biotherapeutics, Natick, MA 01760, USA.
²⁰ Protein Chemistry, Biogen Idec, Cambridge, MA 02142, USA.
²¹ Global Biomarker and Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA.
²² Biologics Drug Discovery, Biogen Idec, Cambridge, MA 02142, USA.
²³ Neurology Research, Biogen Idec, Cambridge, MA 02142, USA.
²⁴ Department of Neurology, Erasmus MC, University Medical Centre, Rotterdam, Netherlands.
²⁵ Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA 94158, USA.
²⁶ Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
²⁷ Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁸ Department of Pathophysiology and Transplantation, "Dino Ferrari" Centre, Università degli Studi di Milano, Milan, Italy.
²⁹ Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA.
³⁰ Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
³¹ Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322, USA.
³² Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. petrucelli.leonard@mayo.edu.

PMID: 28356511
PMCID: PMC5576451
DOI: 10.1126/scitranslmed.aai7866

Abstract

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G₄C₂ repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G₄C₂ repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G₄C₂ RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G₄C₂ RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G₄C₂ RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G₄C₂ RNA and downstream G₄C₂ RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G₄C₂ RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

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Conflict of interest statement

Competing interests: Anti-GP antibodies generated by T.F.G. and L. Petrucelli that were used in this study have been licensed to commercial entities. T.F.G. and L. Petrucelli have a U.S. patent #9,448,232 entitled “Methods and materials for detecting C9ORF72 hexanucleotide repeat expansion positive frontotemporal lobar degeneration or C9ORF72 hexanucleotide repeat expansion positive amyotrophic lateral sclerosis.” A.L.B. is an advisory board member for Biogen and Ionis Pharmaceuticals, is a paid consultant for Ionis Pharmaceuticals, and collaborated with and received research funding from Biogen. A.M. has restricted stock units in Biogen, is a full-time employee of the company, and shared antibodies for this study. B.L.M. is the director of an NIH-sponsored Alzheimer’s Disease Research Center; receives support from University of California, San Francisco/Quest Diagnostics; is the scientific director of the Tau Consortium, the Consortium for Frontotemporal Dementia Research, and the John Douglas French Foundation; is a medical adviser for the Larry L. Hillblom Foundation; and is a scientific advisory board member for the Cambridge Biomedical Research Centre and its subunit, the Biomedical Research Unit in Dementia. B.J.T. has a paid consulting relationship with the Brain Science Institute, Department of Neurology, Johns Hopkins; receives intramural funding from the NIH (Z01-AG000949); and has a patent EP #2751284 B1 entitled “Method for diagnosing a neurodegenerative disease.” C.A. holds shares in Biogen stock. F.R. is a paid employee of Ionis Pharmaceuticals and provided ASOs for the study. J.D.B. is an unpaid adviser to ALS One (a Massachusetts ALS nonprofit organization), an unpaid member of the executive committee for the Northeast ALS Consortium, and an unpaid expert panel member of the U.S. National ALS Registry; has been a paid consultant to Neuraltus Pharmaceuticals and Biogen; and holds the Massachusetts General Hospital–Voyager Therapeutics academic-industry fellow position (a research collaboration paid through appointment at Massachusetts General Hospital). M.G. is a governing board member of the International Society for Frontotemporal Dementia and is on the medical advisory board of the Association for Frontotemporal Dementias. M.K.F. has a paid consulting relationship with Department of Neurology, Uniformed Services University of Health Sciences as an adjunct associate professor. R.B. is the president of and holds stock options in Iron Horse Diagnostics Inc. R.H.B. is affiliated with the Angel Fund for ALS Research. S.L. has a paid consulting relationship with Barrow Neurological Institute and is an associate professor of Neurology in the University of Arizona College of Medicine, the Creighton University Medical School, and Sanofi Genzyme, for unrelated disorders. T.M.M. is a paid consultant for Cytokinetics and receives research support from Ionis Pharmaceuticals and Biogen Idec. V.S. serves on the board of Cytokinetics for the VITALITY trial in ALS and has received consultation fees. All other authors declare that they have no competing interests.

Figures

**Fig. 1. Poly(GP) is detected in CSF from asymptomatic and symptomatic *C9ORF72* repeat expansion carriers**
(A) Poly(GP) in CSF from *C9ORF72* repeat expansion carriers (C9+; n = 134) and noncarriers (C9−; n = 120). ****P < 0.0001, as assessed by van Elteren stratified Wilcoxon rank sum test. (B) CSF poly(GP) concentrations in asymptomatic *C9ORF72* mutation carriers (ASX; n = 27) and symptomatic c9ALS patients with or without comorbid FTD (SX; n = 83). No significant difference in poly(GP) between ASX and SX subjects was observed using a linear regression model adjusted for gender and age at CSF collection. Red lines denote the median.

**Fig. 2. Longitudinal trajectory of poly(GP) in CSF**
Poly(GP) in CSF collected longitudinally from 33 *C9ORF72* repeat expansion carriers who either were asymptomatic or had c9ALS or c9ALS-FTD. Twenty-four subjects had two measurements, 6 had three measurements, 2 had four measurements, and 1 had five measurements. One patient (denoted by red circles) converted from a clinical diagnosis of ALS to ALS-FTD between the first and second CSF collection.

**Fig. 3. Poly(GP) is detected in PBMCs from *C9ORF72* mutation carriers, and c9ASO-1 treatment decreases poly(GP) in lymphoblastoid cell lines**
(A to C) Poly(GP) in lysates from PBMCs from *C9ORF72* mutation carriers (C9+; n = 36) or noncarriers (C9−; n = 34) (A) or in lysates and media from lymphoblastoid cell lines (LCLs) from C9+ (n = 12) or C9− (n = 7) subjects. For (A) and (B), the red line indicates the median. **P < 0.01, ****P < 0.0001, Wilcoxon rank sum test. For (C), a significant correlation was observed between extracellular and intracellular poly(GP) (Spearman’s r = 0.77, P = 0.004, n = 12). (D to F) Two C9+ LCLs were treated with 5 μM nontargeting control ASO (CTL ASO) or one that targets G₄C₂ repeat–containing RNA (c9ASO-1) for 10 days. After treatment, RNA was extracted from cells to measure mRNA of *C9ORF72* variants (D), sister cells were subjected to RNA fluorescence in situ hybridization for the detection of G₄C₂ RNA–positive foci (E), or cell lysates were prepared for analysis of poly(GP) (F). For (D) to (F), *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, unpaired, two-tailed t test. Error bars represent SEM for the three replicates for each cell line. a.u., arbitrary units. Scale bar, 10 μm.

**Fig. 4. c9ASO-2 treatment decreases intracellular and extracellular poly(GP) in c9ALS iPSC neurons**
(A) Poly(GP) in lysates and media from cultured iPSNs derived from *C9ORF72* repeat expansion carriers (C9+; n = 7) and noncarriers (C9−; n = 3). Red horizontal lines indicate the median. *P < 0.05, Wilcoxon rank sum test. (B) A significant correlation was observed between extracellular and intracellular poly(GP) in the c9ALS iPSN lines (Spearman’s r = 0.86, P = 0.02, n = 7). (C to E) At day 45 of differentiation, three c9ALS iPSN lines were treated with a control ASO or an ASO targeting intron 1 of *C9ORF72* (c9ASO-2) at the indicated concentrations. Media were collected before treatment (day 0) and every 5 days thereafter. On day 20, RNA or protein was prepared from cells. (C) Total *C9ORF72* or repeat-containing *C9ORF72* mRNA transcripts. *P < 0.05, ***P < 0.001, one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparisons test. (D) Poly(GP) in c9ALS iPSN media at different time points after treatment initiation (**P < 0.01, ***P < 0.001, ****P < 0.0001, two-way ANOVA) or in cell lysates after the 20-day exposure to c9ASO-2 (**P < 0.01, ***P < 0.001, ****P < 0.0001, one-way ANOVA followed by Tukey’s multiple comparisons test). (E) Intracellular and extracellular poly(GP) in c9ALS iPSNs treated with ASO was significantly correlated (Spearman’s r = 0.99, P < 0.0001, n = 12).

**Fig. 5. Decreased CSF and brain poly(GP) in (G₄C₂)₆₆ mice treated with c9ASO-1**
At 4 to 4.5 months of age, (G₄C₂)₂ mice and (G₄C₂)₆₆ mice were treated with a single intracerebroventricular bolus injection of PBS or c9ASO-1. Eight weeks later, CSF and tissues were harvested from mice for biochemical and immunohistochemical analyses. (A and B) Amount of repeat-containing mRNA or endogenous mouse *C9orf72* mRNA in brain tissue from (G₄C₂)₆₆ mice treated with PBS (n = 11) or c9ASO-1 (n = 9). (C and D) Representative images of RNA foci in the motor cortex of (G₄C₂)₆₆ mice and quantitative analysis of the percentage of foci-positive cells (n = 6 per group). (E and F) Immunohistochemical analysis and quantification of poly(GA), poly(GP), or poly(GR) pathology in the motor cortex of (G₄C₂)₆₆ mice treated with PBS (n = 6) or c9ASO-1 (n = 5). Scale bar, 10 μm. (G and H) Poly(GA) or poly(GP) in brain homogenates or CSF of (G₄C₂)₆₆ mice treated with PBS (n = 11) or c9ASO-1 (n = 9). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, unpaired, two-tailed t test. Red horizontal lines indicate the median. See also related figs. S3 and S4.

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Comment in

Why antisense could make sense for neurodegeneration.
Massey TH, Robertson NP. Massey TH, et al. J Neurol. 2017 Jul;264(7):1542-1544. doi: 10.1007/s00415-017-8515-y. J Neurol. 2017. PMID: 28516330 Free PMC article. No abstract available.
Specific biomarkers for C9orf72 FTD/ALS could expedite the journey towards effective therapies.
Balendra R, Moens TG, Isaacs AM. Balendra R, et al. EMBO Mol Med. 2017 Jul;9(7):853-855. doi: 10.15252/emmm.201707848. EMBO Mol Med. 2017. PMID: 28533210 Free PMC article.
Poly(GP) proteins: a potential pharmacodynamic marker in ALS and FTD.
Budini M, Criollo A. Budini M, et al. Ann Transl Med. 2017 Dec;5(24):504. doi: 10.21037/atm.2017.11.03. Ann Transl Med. 2017. PMID: 29299465 Free PMC article. No abstract available.

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Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

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Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

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