Unfolded protein response activation in <i>C9orf72</i> frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells

Gami‐Patel, Priya; Dijken, Irene van; Meeter, Lieke H.H.; Melhem, Shamiram; Morrema, Tjado H. J.; Scheper, Wiep; Swieten, John C. van; Rozemüller, Annemieke; Dijkstra, Anke A.; Hoozemans, Jeroen J. M.

doi:10.1111/bpa.12894

Cited by 23 publications

(18 citation statements)

References 39 publications

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“…The total cellular p62 expression levels inversely correlate with autophagic activity in that p62 stabilization reflects autophagy suppression. Of note, p62 positive aggregates are common in NDDs including C9orf72 associated disease 58 . Consistent with this, p62 stabilization across neurodegenerative cellular and mouse models and upon STAU1 overexpression ( Figs 1 and 3 ) 17 support the mechanistic role for STAU1 in modulating autophagic flux in neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

Staufen blocks autophagy in neurodegeneration

Paul

Dansithong

Gandelman

et al. 2019

Preprint

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Response to cellular stress represents a highly conserved pathway in evolution. Cells respond to stress with modified synthesis of new proteins by the formation of stress granules (SGs), inhibition of translation initiation and by increased recycling of cellular components through autophagy. One of the master regulators of this response is the mechanistic target of rapamycin (mTOR) kinase 1,2 . We recently reported that Staufen1 (STAU1), a stress granule protein, was overabundant in the rare neurodegenerative disorder SCA2 and provided a link between SG formation and autophagy 3 . In cells harboring mutant ATXN2, STAU1 could also be increased by bafilomycin A consistent with impaired autophagosome lysosome fusion 3 . Here we now examine this association and show the molecular mechanism leading to autophagic block in cells with microtubule associated protein tau (MAPT), presenilin 1 (PSEN1), huntingtin (HTT), TAR DNA-binding protein-43 gene (TARDBP) or C9orf72-SMCR8 complex subunit (C9orf72) mutations underlying a great number of neurodegenerative diseases 4-8 . We found that STAU1 overabundance was present in all cell lines and animal models tested, that it was posttranslational, and that it was associated with an increase in phosphorylated mTOR (P-mTOR) and autophagic block. Exogenous expression of STAU1 in wild-type cells was sufficient to reduce autophagic flux by itself. Mechanistically, STAU1 directly interacted with the mTOR-5'UTR and enhanced mTOR translation. As STAU1 itself is degraded by autophagy, this interaction and the resulting autophagic block results in a maladaptive amplifying response to chronic stress. Targeting STAU1 by RNAi decreased mTOR hyperactivity and normalized mTOR downstream targets in dividing cells, post-mitotic neurons and animal models of SCA2 and ALS-TDP-43 or C9orf72 associated neurodegeneration. In summary, STAU1 is necessary and sufficient to mediate a maladaptive cellular stress response and is a novel target for RNAimediated treatment of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Staufen blocks autophagy in neurodegeneration

Paul

Dansithong

Gandelman

et al. 2019

Preprint

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“…In turn, it is plausible that the other stress responses are invoked in response to that inability to resolve through the RQC. Of note are studies finding DPR deposits in brain tissue to correlate with markers of the UPR (63).…”

Section: Discussionmentioning

confidence: 99%

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

Kriachkov

McWilliam

Mintern

et al. 2022

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Hexanucleotide expansion mutations in C9ORF72 are a cause of familial amyotrophic lateral sclerosis. We previously reported that long arginine-rich dipeptide repeats (DPR), mimicking abnormal proteins expressed from the hexanucleotide expansion, caused translation stalling when expressed in cell culture models. Whether this stalling provides a mechanism of pathogenicity remains to be determined. Here we explored the molecular features of DPR-induced stalling and examined whether known regulatory mechanisms of ribosome quality control (RQC) are involved to sense and resolve the stalls. We demonstrate that arginine-containing DPRs lead to stalling in a length dependent manner, with lengths longer than 40 repeats invoking severe translation arrest. Mutational screening of 40xGly-Xxx DPRs shows that stalling is most pronounced where Xxx are positively charged amino acids (Arg or Lys). Through a genome-wide knockout screen we find that genes regulating stalling on polyadenosine mRNA coding for poly-Lys, a canonical RQC substrate, respond differently to the readthrough of arginine-rich DPRs. Indeed, we find evidence that DPR-mediated stalling has no natural regulatory responses even though the stalls may be sensed, as evidenced by an upregulation of RQC gene expression. These findings therefore implicate arginine-rich DPR-mediated stalled ribosomes as posing a particular danger to cellular health and viability.

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“…This pattern was associated with increased mitophagy and apoptosis in the same hippocampal regions. Different clinical data, especially cognitive and neuromaging findings, suggest that the hippocampus is affected both in ALS and FTD (Abdulla et al , 2014; Raaphorst et al , 2015; Gami-Patel et al , 2021; Gómez-Pinedo et al , 2016). The hippocampus is one of the neurogenic niches of the adult brain, which constantly generates neurons throughout life (Eriksson et al , 1998).…”

Section: Discussionmentioning

confidence: 99%

SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10^S59L-related disease

Bannwarth

Ropert

et al. 2021

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CHCHD10 is an ALS/FTD gene, also involved in a large clinical spectrum, that encodes a protein whose precise function within mitochondria is unclear. Here we show that CHCHD10 interacts with the Stomatin-Like Protein 2 (SLP2) to control the stability of the Prohibitin (PHB) complex in the inner mitochondrial membrane. In affected tissues, SLP2 forms aggregates with prohibitins and the instability of the PHB complex results in activation of OMA1 and accelerated OPA1 proteolysis leading to mitochondrial fragmentation, loss of mitochondrial cristae and apoptosis. Abnormal cristae morphogenesis depends on both the PHB complex destabilization leading to MICOS complex instability, via disruption of OPA1/Mitofilin interaction, and the activation of PINK1-mediated pathways. We also show that the increase of mitophagy found in both heart and hippocampus of Chchd10S59L/+ mito-QC mice is PINK1/Parkin-dependent. Thus, SLP2/PHBs aggregates and destabilization of the PHB complex with PINK1 activation are critical in the sequence of events leading to CHCHD10S59L-related disease.

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Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells

Cited by 23 publications

References 39 publications

Staufen blocks autophagy in neurodegeneration

Staufen blocks autophagy in neurodegeneration

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10^S59L-related disease

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Unfolded protein response activation in C9orf72 frontotemporal dementia is associated with dipeptide pathology and granulovacuolar degeneration in granule cells

Cited by 23 publications

References 39 publications

Staufen blocks autophagy in neurodegeneration

Staufen blocks autophagy in neurodegeneration

Arginine-rich C9ORF72 ALS Proteins Stall Ribosomes in a Manner Distinct From a Canonical Ribosome-Associated Quality Control Substrate

SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10S59L-related disease

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SLP2/prohibitins aggregates and instability of the PHB complex are key elements in CHCHD10^S59L-related disease