Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

doi:10.1016/j.neuron.2020.04.011

. 2020 Jul 22;107(2):292-305.e6.

doi: 10.1016/j.neuron.2020.04.011. Epub 2020 May 5.

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Zachary T McEachin¹, Tania F Gendron², Nisha Raj³, María García-Murias⁴, Anwesha Banerjee⁵, Ryan H Purcell³, Patricia J Ward⁵, Tiffany W Todd⁶, Megan E Merritt-Garza⁷, Karen Jansen-West⁶, Chadwick M Hales⁸, Tania García-Sobrino⁹, Beatriz Quintáns⁴, Christopher J Holler¹⁰, Georgia Taylor¹⁰, Beatriz San Millán¹¹, Susana Teijeira¹¹, Toru Yamashita¹², Ryuichi Ohkubo¹³, Nicholas M Boulis¹⁴, Chongchong Xu¹⁵, Zhexing Wen¹⁶, Nathalie Streichenberger¹⁷; Neuro–CEB Neuropathology Network; Brent L Fogel¹⁸, Thomas Kukar¹⁹, Koji Abe¹², Dennis W Dickson⁶, Manuel Arias²⁰, Jonathan D Glass⁸, Jie Jiang⁵, Malú G Tansey²¹, María-Jesús Sobrido⁴, Leonard Petrucelli², Wilfried Rossoll², Gary J Bassell²²

Affiliations

¹ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA. Electronic address: zmceach@emory.edu.
² Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁴ Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
⁵ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
⁷ Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁸ Department of Neurology, Emory University, Atlanta, GA 30322, USA.
⁹ Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
¹⁰ Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
¹¹ Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
¹² Department of Neurology, Okayama University, Okayama, Japan.
¹³ Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
¹⁴ Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.
¹⁵ Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
¹⁶ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
¹⁷ Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon, Lyon, France; Institut NeuroMyogène CNRS UMR 5310.
¹⁸ Department of Neurology & Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹⁹ Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
²⁰ Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain; Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
²¹ Department of Neuroscience, University of Florida, Gainesville, FL 32607, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32607, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32607, USA.
²² Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA. Electronic address: gbassel@emory.edu.

PMID: 32375063
PMCID: PMC8138626
DOI: 10.1016/j.neuron.2020.04.011

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Zachary T McEachin et al. Neuron. 2020.

. 2020 Jul 22;107(2):292-305.e6.

doi: 10.1016/j.neuron.2020.04.011. Epub 2020 May 5.

Authors

Affiliations

¹ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA. Electronic address: zmceach@emory.edu.
² Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
³ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁴ Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
⁵ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁶ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
⁷ Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
⁸ Department of Neurology, Emory University, Atlanta, GA 30322, USA.
⁹ Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
¹⁰ Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
¹¹ Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
¹² Department of Neurology, Okayama University, Okayama, Japan.
¹³ Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
¹⁴ Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.
¹⁵ Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
¹⁶ Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
¹⁷ Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon, Lyon, France; Institut NeuroMyogène CNRS UMR 5310.
¹⁸ Department of Neurology & Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
¹⁹ Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
²⁰ Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain; Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
²¹ Department of Neuroscience, University of Florida, Gainesville, FL 32607, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32607, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32607, USA.
²² Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA. Electronic address: gbassel@emory.edu.

PMID: 32375063
PMCID: PMC8138626
DOI: 10.1016/j.neuron.2020.04.011

Abstract

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.

Keywords: ALS; C9orf72 expansion; FTD; RAN translation; SCA36; antisense oligonucleotide therapy; chimeric DPRs; dipeptide repeats; neurodegeneration.

PubMed Disclaimer

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

**Figure 1:. Poly(GP) is more abundant in patient-derived cellular models of SCA36 compared to c9ALS/FTD.**
**(A)** Schematic of putative dipeptide repeats in SCA36 and c9ALS/FTD. Red asterisk indicates putative DPRs common to both c9ALS/FTD and SCA36. **(B-F)** Immunoassay for poly(GP) in SCA36 fibroblast, lymphoblastoid cell lines (LCL), induced pluripotent stem cell (iPS), 3D forebrain organoid (Day 105), and iPS-derived motor neurons (iPS-MNs). (B-F) Adjusted P-values displayed if not significant; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001; Kruskal-Wallis one way analysis of variance followed by Dunn’s multiple comparison test.

**Figure 2:. Poly(GP) is abundant but does not form insoluble inclusions in SCA36 postmortem tissue.**
**(A)** poly(GP) is detectable throughout the CNS of SCA36 patients. **(B-E)** poly(GP) is expressed at similar or increased abundance in SCA36 samples compared to c9ALS/FTD samples in disease relevant CNS regions (Cb Ctx: n=7 control, n=11 c9ALS/FTD, n=6 SCA36 cases; Cb DN: n=3 control, n=5 c9ALS/FTD, n=3 SCA36 cases; Ft. Ctx: n=7 control, n=11 c9ALS/FTD, n=6 SCA36 cases; Sp Cd: n=3 control, n=3 c9ALS/FTD, n=4 SCA36 cases). **(F)** poly(GP) aggregates in c9ALS/FTD but not SCA36 patient postmortem tissue (n=5 SCA36). Scale Bar: 100 μm. **(G)** poly(GP) is detectable in the urea-soluble fraction of c9ALS/FTD but not SCA36 samples as assessed by dotblot (n=2 control, n=2 c9ALS/FTD, n=4 SCA36 cases). **(H)** Quantitative immunoassay of sequentially fractionated tissue samples reveals poly(GP) predominately exist as a soluble protein species in SCA36 whereas in c9ALS/FTD a large fraction of poly(GP) exists in the insoluble fraction (Cb Ctx: n=4 c9ALS/FTD, n=4 SCA36 cases; Ft. Ctx: n=5 c9ALS/FTD, n=5 SCA36 cases). **(I)** Representative images of granule, Purkinje, and molecular cell layer ROI selection (white ouline) for digital spatial profiling of cerebellar samples. Calbindin and DAPI were used to delineate cerebellar architecture. **(J)** Volcano plots illustrating differentially abundant proteins as determined by digital spatial profiling in the cerebellar granule layer of c9ALS/FTD and SCA36 compared to controls (n=7 c9ALS/FTD, n=5 SCA36, n=7 control cases). Significant proteins (FDR<0.05) are colored. (B to E) *P<0.05, **P<0.005, ***P<0.0005, Kruskal-Wallis one way analysis of variance followed by Dunn’s multiple comparison test.

**Figure 3:. SCA36 produces antisense DPRs but lacks TDP-43 pathology.**
**(A)** The antisense DPR, poly(PR) aggregates in both c9ALS/FTD and SCA36 cerebellar tissue. **(B)** SCA36 frontal cortex tissue lacks TDP43 pathology characteristic of c9ALS/FTD. Scale bars: 50μm, *inset* 10μm. **(C)** pTDP43 is not found in the detergent insoluble, urea soluble fraction of SCA36 patient frontal cortex. #cleavage products, *full-length TDP43, †oligomeric species, ‡high molecular weight species.

**Figure 4:. Expanded TG₃C₂ repeats impair splicing of *NOP56* intron 1 and result in AUG-mediated translation of poly(GP) DPRs in SCA36.**
**(A)** Relative expression of *NOP56* using TaqMan probes spanning exon-exon junctions in control and SCA36 patient cerebellar cortex samples (n=20 control, n=5 SCA36). *NOP56* expression as detected by exon 3-exon 4 or exon 6-exon 7 junction probes is increased in SCA36 compared to controls. In contrast, *NOP56* expression as detected by exon 1-exon 2 junction probes is decreased in SCA36 compared to controls. **(B)** NOP56 protein is increased in SCA36 patient cerebellar cortex compared to controls (n=4 control, n=3 SCA36). *Top*: Western blot analysis of NOP56 and ß-actin. *Bottom*: Quantification of NOP56 protein in control and SCA36 samples relative to ß-actin. **(C)** Relative expression of *NOP56* using a TaqMan probe spanning the intron 1 - exon 2 junction in control and SCA36 patient cerebellar cortex samples (n=9 control, n=6 SCA36). **(D)** *NOP56* transcripts containing a retained intron 1 but not intron 4 or intron 10 is increased in SCA36 compared to control (n=9 control, n=6 SCA36) as detected by Nanostring. **(E)** Alignment of the 5’ flanking sequence of intron 1 from the expanded allele of SCA36 cases. **(F)** Schematic figure of (GGCCTG)₈₂ NanoLuc (NLuc) reporter constructs. **(G)** Expression of ATG (GGCCTG)₈₂ NanoLuc reporter constructs (n=3 biological replicates). Values normalized to co-transected firefly luciferase (FLuc). **(H)** Expression of 6x Stop and ATG - (GGCCTG)₈₂ NanoLuc reporter constructs for the +1 (GL) and +2 (WA) frame (n=3 biological replicates). Data are presented as mean ± SEM. (A-D) *P<0.05, **P<0.005, ***P<0.0005, ****P<0.0001, Mann-Whitney test. (G) ***P<0.0005, ordinary one-way ANOVA. (H) *P<0.05, unpaired Student’s t-test.

**Figure 5:. Chimeric peptides underlie divergent DPR pathology in c9ALS/FTD and SCA36.**
**(A)** poly(GP) immunohistochemistry in AAV-GFP and AAV-GP_80x-GFP; poly(GP) is diffuse throughout the CNS after 2 months *in vivo*. Scale bars: 100μm, *inset* 50μm. **(B)** poly(GA) and poly(GP) colocalize in perinuclear aggregates in the frontal cortex of a c9ALS/FTD patients and c9BAC mice. **(C)** Schematic illustrating putative mechanisms of poly(GA)-mediated poly(GP) aggregation. **(D)** Immunofluorescence for GFP 48 hours after transfection in HEK293T cells expressing GP_80x-GFP or chimeric GA_50xGP_50x-GFP to assess the aggregation propensity of a chimeric GAGP peptide. Scale bar: 10μm. **(E)** Immunoblot for the indicated proteins to determine whether GP_80x-GFP, GA_80x-GFP, chimeric GA_50xGP₅₀-GFP, or 1:1 co-transfection of GP_80x-GFP and GA_80x-HA is present in the soluble (S) or insoluble (In) fraction. **(F)** Schematic illustrating the meso-scale discovery (MSD) immunoassay developed to detect chimeric DPRs. **(G)** A traditional GA/GA MSD assay or a chimeric peptide detecting GA/GP immunoassay was used to detect poly(GA) or chimeric poly(GA:GP) DPRs in the detergent insoluble, urea soluble fraction from control (n=3 cases), c9ALS/FTD (n=4 cases), or SCA36 (n=5 cases) patient frontal cortex and **(H)** detergent-insoluble, urea-soluble fraction from control (n=3 cases) and c9ALS/FTD (n=6 cases) patient cerebellar cortex. (G, H) *p<0.05, **p<0.005, Kruskal-Wallis one way analysis of variance followed by pairwise one-tailed Mann-Whitney Test.

**Figure 6:. Antisense oligonucleotides reduce poly(GP) in patient derived cellular models of SCA36.**
**(A-D)** Dose-response curves were generated by treating SCA36 fibroblast (n=3 patient cell lines) with described concentrations. UTC=untransfected control. **(A)** Dose-response curves show robust reduction of poly(GP) by *NOP56* intron 1 (ASO-#1) or TG₃C₂ (ASO-#2) targeting ASOs (see Figure S10A and Table S2). **(B)** *NOP56* mRNA levels as measured by exon 1 – exon 2 junction probes are not reduced at 1nM or 10nM ASO concentrations. **(C)** NOP56 protein is not significantly reduced at 0.1nM, 1nM, or 10nM ASO concentrations. **(D)** poly(GP) is reduced at 10nM ASO concentrations relative to a scrambled control. (A) to (D) n=3 SCA36 patient fibroblast cell lines, treated for 48 hours at respective concentrations. **(E, F)** SCA36 fibroblast (n=2 patient cell lines) and LCLs (n=2 patient cell lines) were treated with 5μM non-targeting control ASO or an ASO targeting intron 1 of *NOP56* delivered via gymnosis. Protein lysates were collected 10 days after treatment and poly(GP) levels measured. Data are presented as mean ± SEM; (B) to (E), *P<0.05, **P<0.01, ***P<0.001 one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparisons test. **(G)** poly(GP) is detectable in cerebrospinal fluid (CSF) from c9ALS/FTD (n=5), and SCA36 patients (n=5) but not healthy controls (n=5).

**Figure 7:. Model of divergent translation and pathology of dipeptide repeats in c9ALS/FTD and SCA36.**
The c9ALS/FTD-associated G₄C₂ and SCA36-associated TG₃C₂ repeat expansions are similarly positioned in the first intron of the genes *C9orf72* and *NOP56*, respectively; however, the flanking genetic context of these repeat expansions differ. With respect to *C9orf72*, the 5’ intron sequence flanking the G₄C₂ repeat contains a near-cognate CUG start codon. In c9ALS/FTD, translational initiation at this near-cognate start codon, either from a retained mRNA transcript variant or a spliced and exported intron 1 RNA species, would preferentially produce a poly(GA) dipeptide repeat (DPR) protein. In contrast, *NOP56* intron 1 is located between two coding exons, thus retention of intron 1 harboring a TG₃C₂ expansion would produce a novel *NOP56* transcript variant that would preferentially produce a poly(GP) DPR protein via canonical AUG-mediated translation. Translational frameshifting and/or genetic aberrations in the respective repeat expansions result in chimeric DPR (cDPR) species. In c9ALS/FTD, these chimeric species would results in homogenous poly(GA) DPRs and/or GA-rich poly(GA:GP) cDPRs that result in poly(GA) and poly(GP) inclusions as seen in c9ALS/FTD patient samples. In SCA36, homogenous poly(GP) DPRs and/or GP-rich cDPRs would result in soluble poly(GP) as seen in SCA36 patient samples.

See this image and copyright information in PMC

Comment in

It Takes Two to Tango: DPRs in ALS and SCA36.
Maharjan N, Saxena S. Maharjan N, et al. Neuron. 2020 Jul 22;107(2):202-204. doi: 10.1016/j.neuron.2020.06.025. Neuron. 2020. PMID: 32702342

Cited by

Measuring Repeat-Associated Non-AUG (RAN) Translation.
Wang S, Sun S. Wang S, et al. Methods Mol Biol. 2022;2428:113-132. doi: 10.1007/978-1-0716-1975-9_8. Methods Mol Biol. 2022. PMID: 35171477
Interactome screening of C9orf72 dipeptide repeats reveals VCP sequestration and functional impairment by polyGA.
Božič J, Motaln H, Janež AP, Markič L, Tripathi P, Yamoah A, Aronica E, Lee YB, Heilig R, Fischer R, Thompson AJ, Goswami A, Rogelj B. Božič J, et al. Brain. 2022 Apr 18;145(2):684-699. doi: 10.1093/brain/awab300. Brain. 2022. PMID: 34534264 Free PMC article.
pTDP-43 levels correlate with cell type specific molecular alterations in the prefrontal cortex of C9orf72 ALS/FTD patients.
Wang HV, Xiang JF, Yuan C, Veire AM, Gendron TF, Murray ME, Tansey MG, Hu J, Gearing M, Glass JD, Jin P, Corces VG, McEachin ZT. Wang HV, et al. bioRxiv [Preprint]. 2024 Jun 13:2023.01.12.523820. doi: 10.1101/2023.01.12.523820. bioRxiv. 2024. PMID: 36711601 Free PMC article. Preprint.
Impaired ribosome-associated quality control of C9orf72 arginine-rich dipeptide-repeat proteins.
Viera Ortiz AP, Cajka G, Olatunji OA, Mikytuck B, Shalem O, Lee EB. Viera Ortiz AP, et al. Brain. 2023 Jul 3;146(7):2897-2912. doi: 10.1093/brain/awac479. Brain. 2023. PMID: 36516294 Free PMC article.
CGG repeats trigger translational frameshifts that generate aggregation-prone chimeric proteins.
Wright SE, Rodriguez CM, Monroe J, Xing J, Krans A, Flores BN, Barsur V, Ivanova MI, Koutmou KS, Barmada SJ, Todd PK. Wright SE, et al. Nucleic Acids Res. 2022 Aug 26;50(15):8674-8689. doi: 10.1093/nar/gkac626. Nucleic Acids Res. 2022. PMID: 35904811 Free PMC article.

See all "Cited by" articles

References

1. Almeida S, Krishnan G, Rushe M, Gu Y, Kankel MW, and Gao F-B (2019). Production of poly(GA) in C9ORF72 patient motor neurons derived from induced pluripotent stem cells. Acta Neuropathologica 138, 1099–1101. - PMC - PubMed
1. Arias M, Arias-Rivas S, Blanco-Arias P, Dapena D, Vazquez F, and Rossi M (2008). SCA from the Costa da Morte: A new SCA. Description of the phenotype. Neurologia 23, 628–629.
1. Arias M, Garcia-Murias M, and Sobrido MJ (2017). Spinocerebellar ataxia 36 (SCA36): <<Costa da Morte ataxia>>. Neurologia 32, 386–393. - PubMed
1. Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R, et al. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646. - PMC - PubMed
1. Banez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, Pletnikova O, Borchelt DR, Ross CA, Margolis RL, et al. (2015). RAN Translation in Huntington Disease. Neuron 88, 667–677. - PMC - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

[1] Almeida S, Krishnan G, Rushe M, Gu Y, Kankel MW, and Gao F-B (2019). Production of poly(GA) in C9ORF72 patient motor neurons derived from induced pluripotent stem cells. Acta Neuropathologica 138, 1099–1101. - PMC - PubMed

[2] Almeida S, Krishnan G, Rushe M, Gu Y, Kankel MW, and Gao F-B (2019). Production of poly(GA) in C9ORF72 patient motor neurons derived from induced pluripotent stem cells. Acta Neuropathologica 138, 1099–1101. - PMC - PubMed

[3] Arias M, Arias-Rivas S, Blanco-Arias P, Dapena D, Vazquez F, and Rossi M (2008). SCA from the Costa da Morte: A new SCA. Description of the phenotype. Neurologia 23, 628–629.

[4] Arias M, Arias-Rivas S, Blanco-Arias P, Dapena D, Vazquez F, and Rossi M (2008). SCA from the Costa da Morte: A new SCA. Description of the phenotype. Neurologia 23, 628–629.

[5] Arias M, Garcia-Murias M, and Sobrido MJ (2017). Spinocerebellar ataxia 36 (SCA36): <<Costa da Morte ataxia>>. Neurologia 32, 386–393. - PubMed

[6] Arias M, Garcia-Murias M, and Sobrido MJ (2017). Spinocerebellar ataxia 36 (SCA36): <<Costa da Morte ataxia>>. Neurologia 32, 386–393. - PubMed

[7] Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R, et al. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646. - PMC - PubMed

[8] Ash PE, Bieniek KF, Gendron TF, Caulfield T, Lin WL, Dejesus-Hernandez M, van Blitterswijk MM, Jansen-West K, Paul JW 3rd, Rademakers R, et al. (2013). Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646. - PMC - PubMed

[9] Banez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, Pletnikova O, Borchelt DR, Ross CA, Margolis RL, et al. (2015). RAN Translation in Huntington Disease. Neuron 88, 667–677. - PMC - PubMed

[10] Banez-Coronel M, Ayhan F, Tarabochia AD, Zu T, Perez BA, Tusi SK, Pletnikova O, Borchelt DR, Ross CA, Margolis RL, et al. (2015). RAN Translation in Huntington Disease. Neuron 88, 667–677. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Affiliations

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Conflict of interest statement

Figures

Comment in

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous