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

McEachin, Zachary T.; Gendron, Tania F.; Raj, Nisha; García-Murias, Maria; Banerjee, Anwesha; Purcell, Ryan H.; Ward, Patricia J.; Todd, Tiffany W.; Merritt-Garza, Megan E.; Jansen-West, Karen; Hales, Chadwick M.; García-Sobrino, Tania; Quintáns, Beatriz; Holler, Christopher J.; Taylor, Georgia; Millán, Beatriz San; Teijeira, Susana; Yamashita, Toru; Ohkubo, Ryuichi; Boulis, Nicholas M.; Xu, Chi; Wen, Zhexing; Streichenberger, Nathalie; Fogel, Brent L.; Kukar, Thomas; Abe, Kōji; Dickson, Dennis W.; Arias, Manuel; Glass, Jonathan D.; Jiang, Jie; Tansey, Malú G.; Sobrido, María‐Jesús; Petrucelli, Leonard; Rossoll, Wilfried; Bassell, Gary J.

doi:10.1016/j.neuron.2020.04.011

Cited by 52 publications

(45 citation statements)

References 62 publications

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“…Future work will be needed to determine the selective effects that these sequence modifications have on the biophysical properties of RAN translated proteins and their exact roles in disease pathogenesis in ALS and FTD. When coupled with recent findings in FXTAS [31] and Spinocerebellar Ataxia type 36 [67,68], these findings suggest that similar analyses in other repeat disorders are likely warranted.…”

Section: Discussionsupporting

confidence: 56%

The carboxyl termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD

Flores

Krans

et al. 2020

acta neuropathol commun

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An intronic hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This repeat is thought to elicit toxicity through RNA mediated protein sequestration and repeat-associated non-AUG (RAN) translation of dipeptide repeat proteins (DPRs). We generated a series of transgenic Drosophila models expressing GGGGCC (G 4 C 2) repeats either inside of an artificial intron within a GFP reporter or within the 5′ untranslated region (UTR) of GFP placed in different downstream reading frames. Expression of 484 intronic repeats elicited minimal alterations in eye morphology, viability, longevity, or larval crawling but did trigger RNA foci formation, consistent with prior reports. In contrast, insertion of repeats into the 5′ UTR elicited differential toxicity that was dependent on the reading frame of GFP relative to the repeat. Greater toxicity correlated with a short and unstructured carboxyl terminus (C-terminus) in the glycine-arginine (GR) RAN protein reading frame. This change in C-terminal sequence triggered nuclear accumulation of all three RAN DPRs. A similar differential toxicity and dependence on the GR C-terminus was observed when repeats were expressed in rodent neurons. The presence of the native C-termini across all three reading frames was partly protective. Taken together, these findings suggest that C-terminal sequences outside of the repeat region may alter the behavior and toxicity of dipeptide repeat proteins derived from GGGGCC repeats.

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Section: Discussionsupporting

confidence: 56%

The carboxyl termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD

Flores

Krans

et al. 2020

acta neuropathol commun

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“…Immunoblots were performed as previously described [27,55,72]. Briefly, human and mouse brain running samples were prepared in loading buffer with 50 mM 2-Mercaptoethanol (BME) followed by denaturing at 70 °C for 15 min.…”

Section: Immunoblotmentioning

confidence: 99%

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Huang

Modeste

Dammer

et al. 2020

acta neuropathol commun

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Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.

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“…Yet, concrete structural mechanisms of macromolecular inhibition for these possible pathways remain to be determined. Our findings of strong atomic interactions between the arginine-containing DPR proteins and the ribosome, and impairment of the central ribosome function, suggest a direct structural mechanism for cellular toxicity in C9ORF72-ALS/FTD and possibly in spinocerebellar ataxia type 36 (SMA36) where accumulation of poly-PR has recently been observed (McEachin et al, 2020).…”

Section: Discussionmentioning

confidence: 81%

Ribosome inhibition byC9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

Loveland

Svidritskiy

Susorov

et al. 2020

Preprint

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Toxic dipeptide repeat (DPR) proteins are produced from expanded G4C2 hexanucleotide repeats in the C9ORF72 gene, which cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Two DPR proteins, poly-PR and poly-GR, repress cellular translation but the molecular mechanism remains unknown. Here we show that poly-PR and poly-GR of ≥ 20 repeats inhibit the ribosome’s peptidyl-transferase activity at nanomolar concentrations, comparable to specific translation inhibitors. High-resolution cryo-EM structures reveal that poly-PR and poly-GR block the polypeptide tunnel of the ribosome, extending into the peptidyl-transferase center. Consistent with these findings, the macrolide erythromycin, which binds in the tunnel, competes with the DPR proteins and restores peptidyl-transferase activity. Our results demonstrate that strong and specific binding of poly-PR and poly-GR in the ribosomal tunnel blocks translation, revealing the structural basis of their toxicity in C9ORF72-ALS/FTD.

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

Cited by 52 publications

References 62 publications

The carboxyl termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD

The carboxyl termini of RAN translated GGGGCC nucleotide repeat expansions modulate toxicity in models of ALS/FTD

Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

Ribosome inhibition byC9ORF72-ALS/FTD-associated poly-PR and poly-GR proteins revealed by cryo-EM

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