C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy

Cali, Christopher P.; Patino, Maribel; Tai, Yee Kit; Ho, Wan Yun; McLean, Catriona; Morris, Christopher M.; Seeley, William W.; Miller, Bruce L.; Gaig, Carles; Vonsattel, Jean Paul; White, Charles L.; Roeber, Sigrun; Kretzschmar, Hans A.; Troncoso, Juan C.; Troakes, Claire; Gearing, Marla; Ghetti, Bernardino; Deerlin, Vivianna M. Van; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Mok, Kin Y.; Ling, Helen; Dickson, Dennis W.; Schellenberg, Gerard D.; Ling, Shuo; Lee, Edward B.

doi:10.1007/s00401-019-02045-5

Cited by 53 publications

(61 citation statements)

References 94 publications

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“…Intriguingly, in individuals with small repeat sizes (< 5 kb), we detected relatively high C9orf72 expression levels, including an outlier with expression levels above 200%. These findings are in accordance with other descriptions of subjects with intermediate or small expansions who exhibit normal to elevated expression levels [8,[22][23][24]. In general, though, we did not detect an association between the length of the C9orf72 repeat expansion and methylation or expression levels, which contradicts other reports [11].…”

Section: Discussionsupporting

confidence: 89%

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Jackson

Finch

Baker

et al. 2020

Mol Neurodegeneration

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Background: A repeat expansion in the C9orf72-SMCR8 complex subunit (C9orf72) is the most common genetic cause of two debilitating neurodegenerative diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Currently, much remains unknown about which variables may modify these diseases. We sought to investigate associations between C9orf72 promoter methylation, RNA expression levels, and repeat length, their potential effects on disease features, as well as changes over time and within families.Methods: All samples were obtained through the ALS Center at Mayo Clinic Florida. Our primary cohort included 75 unrelated patients with an expanded C9orf72 repeat, 33 patients who did not possess this expansion, and 20 control subjects without neurodegenerative diseases. Additionally, 67 members from 17 independent C9orf72 families were selected of whom 33 harbored this expansion. Longitudinally collected samples were available for 35 C9orf72 expansion carriers. To increase our understanding of C9orf72-related diseases, we performed quantitative methylation-sensitive restriction enzyme-based assays, digital molecular barcoding, quantitative real-time PCR, and Southern blotting.

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Section: Discussionsupporting

confidence: 89%

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Jackson

Finch

Baker

et al. 2020

Mol Neurodegeneration

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“…Our study, along with the above‐mentioned previous studies, shows that C9orf72 is an effective autophagy regulator that can play multiple roles in the regulation of autophagy. Importantly, a recent study showed that overexpression of C9orf72 may enhance autophagy initiation under normal condition, but may impair autophagy under stress conditions (Cali et al, 2019). Interestingly, we found that loss of C9orf72 (opposite to C9orf72 overexpression) might enhance neuronal autophagy under stress condition (Figure d).…”

Section: Discussionmentioning

confidence: 99%

C9orf72 associates with inactive Rag GTPases and regulates mTORC1‐mediated autophagosomal and lysosomal biogenesis

Wang

Tao

et al. 2020

Aging Cell

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GGGGCC repeat expansion inC9orf72 is the most common genetic cause in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two neurodegenerative disorders in association with aging. Bidirectional repeat expansions in the noncoding region of C9orf72 have been shown to produce dipeptide repeat (DPR) proteins through repeat-associated non-ATG (RAN) translation and to reduce the expression level of the C9orf72 gene product, C9orf72 protein. Mechanisms underlying C9orf72-linked neurodegeneration include expanded RNA repeat gain of function, DPR toxicity, and C9orf72 protein loss of function. In the current study,we focus on the cellular function of C9orf72 protein. We report that C9orf72 can regulate lysosomal biogenesis and autophagy at the transcriptional level. We show that loss of C9orf72 leads to striking accumulation of lysosomes, autophagosomes, and autolysosomes in cells, which is associated with suppressed mTORC1 activity and enhanced nuclear translocation of MiT/TFE family members MITF, TFE3, and TFEB, three master regulators of lysosomal biogenesis and autophagy. We demonstrate that the DENN domain of C9orf72 specifically binds to inactive Rag GTPases, but not active Rag GTPases, thereby affecting the function of Rag/raptor/mTOR complex and mTORC1 activity. Furthermore, active Rag GTPases, but not inactive Rag GTPases or raptor rescued the impaired activity and lysosomal localization of mTORC1 in C9orf72-deficient cells. Taken together, the present study highlights a key role of C9orf72 in lysosomal and autophagosomal regulation, and demonstrates that Rag GTPases and mTORC1 are involved in C9orf72-mediated autophagy.

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“…The different thresholds have been justified in many ways, e.g. association with the same risk haplotype as expansions (≥ 7 repeats) [ 24 ], effects on DNA methylation and gene expression (7–24 and 17–29 repeats) [ 3 , 9 ] and associations with neurodegenerative diseases (e.g. 17–30, 20–22, 20–30, 24–30) [ 3 , 10 , 12 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

Kaivola

Salmi

Jansson

et al. 2020

acta neuropathol commun

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The hexanucleotide repeat expansion in intron 1 of the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson’s disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the C9orf72 repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7–45, 17–45, 21–45, 24–45 and 24–30). The carriership of an intermediate-length allele did not associate with ALS (Fisher’s test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18–65, 66–84 and 85–105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02–14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79–61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

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C9orf72 intermediate repeats are associated with corticobasal degeneration, increased C9orf72 expression and disruption of autophagy

Abstract: Author Contributions: E.B.L. and conceived and designed this study. C.P.C performed RNA and protein expression experiments in patient brain and iPSCs. M.P. carried out screen for repeat size and risk allele genotype. J.M.P. performed tau biosensor cell experiments.

Cited by 53 publications

References 94 publications

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

Elevated methylation levels, reduced expression levels, and frequent contractions in a clinical cohort of C9orf72 expansion carriers

C9orf72 associates with inactive Rag GTPases and regulates mTORC1‐mediated autophagosomal and lysosomal biogenesis

Carriership of two copies of C9orf72 hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population

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