Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

Nguyen, Lien; Montrasio, Fabio; Pattamatta, Amrutha; Tusi, Solaleh Khoramian; Bardhi, Olgert; Meyer, Kevin D.; Hayes, Lindsey R.; Nakamura, Katsuya; Báñez-Coronel, Mónica; Coyne, Alyssa N.; Guo, Shan; Laboissonniere, Lauren A.; Gu, Yuanzheng; Narayanan, Saravanakumar; Smith, Benjamin; Nitsch, Roger M.; Kankel, Mark W.; Rushe, Mia; Rothstein, Jeffrey D.; Zu, Tao; Grimm, Jan; Ranum, Laura P.W.

doi:10.1016/j.neuron.2019.11.007

Cited by 80 publications

(75 citation statements)

References 62 publications

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“…We cannot exclude that poly‐GA expression triggers additional indirect effects in vivo , for example by directly releasing other molecules that promote TDP‐43 aggregation in neighboring cells or triggering release of such factors from glial cells. Our findings provide mechanistic insights into very recent active and passive antibody therapy approaches in C9orf72 mouse models by us and others (Nguyen et al , ; Zhou et al , ). Nguyen et al () also reported that anti‐GA antibodies partially restore proteasome function in poly‐GA‐expressing cells and show that antibodies clear poly‐GA via the proteasome and autophagy pathway depending on the intracellular Fc‐receptor TRIM21.…”

Section: Discussionsupporting

confidence: 68%

“…Our findings provide mechanistic insights into very recent active and passive antibody therapy approaches in C9orf72 mouse models by us and others (Nguyen et al , ; Zhou et al , ). Nguyen et al () also reported that anti‐GA antibodies partially restore proteasome function in poly‐GA‐expressing cells and show that antibodies clear poly‐GA via the proteasome and autophagy pathway depending on the intracellular Fc‐receptor TRIM21. Moreover, boosting proteasome function in donor and receiver cells with small molecules such as rolipram may overcome poly‐GA‐induced proteasome impairment and lead to clearance of ubiquitinated substrates such as TDP‐43.…”

Section: Discussionsupporting

confidence: 68%

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Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

et al. 2020

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The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development.Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 68%

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

et al. 2020

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“…These C9-BAC mice were recently used to demonstrate that a human antibody targeting the GA RAN protein is sufficient to rescue behavior and survival phenotypes, without changing the levels of their corresponding expansion RNAs. These preclinical data highlight the therapeutic potential of targeting RAN proteins (Nguyen et al, 2020).…”

Section: Discussionmentioning

confidence: 82%

“…Similar to our previously published data on mice with shorter repeat tracts (29-37 repeats) (Liu et al, 2016), sense and antisense RNA foci were not detected in animals in the C9-50 line (Fig 5A, B). Next, we compared RAN protein aggregates in the retrosplenial cortex by immunohistochemistry (IHC) or immunofluorescence (IF) using human α-GA1 and α-GP1 antibodies (Nguyen, Montrasio et al, 2020) (Fig 5C, S8A). At 40 weeks of age, there was a significant increase in percentage of cells with polyGA aggregates (71% vs 40%) and polyGP aggregates (22% vs. 15%) detected by IHC or IF in the C9-800 compared to the C9-500 mice (Fig 5C-E) while no GA or GP aggregates were detected in the C9-50 sub-line consistent with the decreased penetrance in this sub-line.…”

Section: Bac Micementioning

confidence: 99%

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice

Pattamatta

Nguyen

Olafson

et al. 2020

Preprint

Self Cite

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C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease.BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes.Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G4C2 repeats generated from the single-copy C9-500 line show longer repeats result in earlier onset, increased disease penetrance, and increased levels of RNA foci and RAN aggregates. These data demonstrate G4C2 repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.

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“…To remove any traces of disordered hSOD1 in the native samples we performed two sequential incubations (1′ and 2′) of each sample. Input (1/200th of total input), non-bound (n.b., 1/200th of sample) and immunocaptured (i.c., 1/200th of sample) fractions were immunoblotted using rabbit antibody targeting aa 24-39 of hSOD1 (rbAb αSOD1 [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Figure S1a for a full view of the filter. f The human SOD1 (hSOD1) peptide sequences used for immunization aligned to the murine SOD1 (mSOD1) epitope sequences.…”

Section: Verification Of Mab Binding To Spinal Cord-derived Hsod1 Aggmentioning

confidence: 99%

Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice

Lehmann

Marklund

Bolender

et al. 2020

acta neuropathol commun

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Increasing evidence suggests that propagation of the motor neuron disease amyotrophic lateral sclerosis (ALS) involves the pathogenic aggregation of disease-associated proteins that spread in a prion-like manner. We have identified two aggregate strains of human superoxide dismutase 1 (hSOD1) that arise in the CNS of transgenic mouse models of SOD1-mediated ALS. Both strains transmit template-directed aggregation and premature fatal paralysis when inoculated into the spinal cord of adult hSOD1 transgenic mice. This spread of pathogenic aggregation could be a potential target for immunotherapeutic intervention. Here we generated mouse monoclonal antibodies (mAbs) directed to exposed epitopes in hSOD1 aggregate strains and identified an aggregate selective mAb that targets the aa 143–153 C-terminal extremity of hSOD1 (αSOD1143–153). Both pre-incubation of seeds with αSOD1143–153 prior to inoculation, and weekly intraperitoneal (i.p.) administration attenuated transmission of pathogenic aggregation and prolonged the survival of seed-inoculated hSOD1G85R Tg mice. In contrast, administration of a mAb targeting aa 65–72 (αSOD165–72), which exhibits high affinity towards monomeric disordered hSOD1, had an adverse effect and aggravated seed induced premature ALS-like disease. Although the mAbs reached similar concentrations in CSF, only αSOD1143–153 was found in association with aggregated hSOD1 in spinal cord homogenates. Our results suggest that an aggregate-selective immunotherapeutic approach may suppress seeded transmission of pathogenic aggregation in ALS. However, long-term administration of αSOD1143–153 was unable to prolong the lifespan of non-inoculated hSOD1G85R Tg mice. Thus, spontaneously initiated hSOD1 aggregation in spinal motor neurons may be poorly accessible to therapeutic antibodies.

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Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model

Cited by 80 publications

References 62 publications

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice

Aggregate-selective antibody attenuates seeded aggregation but not spontaneously evolving disease in SOD1 ALS model mice

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