Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

Logan, Todd; Simon, Matthew; Rana, Anil; Cherf, Gerald Maxwell; Srivastava, Ankita; Davis, Sonnet S.; Low, Ray Lieh Yoon; Chiu, Chi-Lu; Fang, Meng; Huang, Fen; Bhalla, Akhil; Llapashtica, Ceyda; Prorok, Rachel; Pizzo, Michelle E.; Calvert, Meredith; Sun, Elizabeth W.; Hsiao‐Nakamoto, Jennifer; Rajendra, Yashas; Lexa, Katrina W.; Srivastava, Divya; Lengerich, Bettina van; Wang, Junhua; Robles-Colmenares, Yaneth; Kim, Dojin; Duque, Joseph; Lenser, Melina; Earr, Timothy; Nguyen, Hoang; Chau, Roni; Tsogtbaatar, Buyankhishig; Ravi, Ritesh; Skuja, Lukas L.; Solanoy, Hilda; Rosen, Howard J.; Boeve, Bradley F.; Boxer, Adam L.; Heuer, Hilary W.; Dennis, Mark S.; Kariolis, Mihalis S.; Monroe, Kathryn M.; Przybyla, Laralynne; Sanchez, Pascal; Meisner, René; Diaz, Dolores; Henne, Kirk R.; Watts, Ryan J.; Henry, Anastasia G.; Gunasekaran, Kannan; Astarita, Giuseppe; Suh, Jung Hee; Lewcock, Joseph W.; DeVos, Sarah L.; Paolo, Gilbert Di

doi:10.1016/j.cell.2021.08.002

Cited by 141 publications

(124 citation statements)

References 76 publications

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“…While we found that HEXA activity was not changed, GBA activity was decreased in the frontal lobes (but not the occipital lobes) of GRN FTLD-TDP patients. Finally, and of particular relevance to our findings of PGRN deficiency causing gangliosidosis, a recent report corroborates reduced BMP levels in brains of PGRN-deficient mice 22 .…”

Section: Discussionsupporting

confidence: 88%

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Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Boland

Swarup

et al. 2021

Preprint

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Homozygous mutations of granulin precursor (GRN) lead to neuronal ceroid lipofuscinosis, a severe neurodevelopmental disease, in humans and neuroinflammation in mice. Haploinsufficiency of GRN almost invariably causes frontotemporal dementia (FTD). The GRN locus produces progranulin (PGRN), a lysosomal precursor protein that is cleaved to granulin peptides. Despite intensive investigation, the function of granulins and the reason why their absence causes neurodegeneration remain unclear. Here, we investigated PGRN function in lipid degradation, a major function of lysosomes. We show that PGRN knockout human cells, PGRN-deficient murine brain, and frontal lobes of human brains from subjects with PGRN deficient FTD have increased levels of gangliosides, highly abundant sialic acid containing glycosphingolipids (GSL) that are degraded in lysosomes. Probing how PGRN deficiency causes these changes, we found normal levels and activities of enzymes that catabolize gangliosides. However, levels of bis(monoacylglycero)phosphate (BMP), a lysosomal lipid required for ganglioside catabolism, were markedly reduced in PGRN deficient cells and brain tissues. These data indicate that granulins are required to maintain BMP levels, which regulate ganglioside catabolism, and that PGRN deficiency in lysosomes leads to gangliosidosis. This aberrant accumulation of gangliosides may contribute to neuroinflammation and neurodegeneration susceptibility.

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Section: Discussionsupporting

confidence: 88%

“…4f ). Binding of PGRN to BMP, recently reported independently 22 , suggests a model in which GRN binding enables BMP recycling from ILVs by shielding it from lysosomal degradation. Whatever the mechanism, low BMP levels impair ganglioside catabolism and result in gangliosidosis.…”

Section: Resultsmentioning

confidence: 86%

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Boland

Swarup

et al. 2021

Preprint

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“…To formally test this, we performed ribosomal profiling experiments to assess the amount of ribosome-bound GRN mRNA, which reflects its rate of translation. We found that cells treated with ASOs M10 and M36 had marked enrichment of GRN mRNA in the heavy polyribosome fractions (11)(12)(13)(14)(15)(16), compared to cells treated with a scrambled control ASO (Fig. 5B), strongly suggesting that these ASOs increase the rate of progranulin translation.…”

Section: Asos Targeting the Mir-29b Binding Site Increase Translation...mentioning

confidence: 80%

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation

Aggarwal

Banerjee

Jones

et al. 2022

Preprint

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Loss-of-function GRN mutations result in progranulin haploinsufficiency and are a common cause of frontotemporal dementia (FTD). Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but ASO-based strategies for increasing target protein levels are still relatively limited. Here, we report the use of ASOs to increase progranulin protein levels by targeting the miR-29b binding site in the 3′ UTR of the GRN mRNA, resulting in increased translation.

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“…Prosaposin, progranulin, and procathepsin are the three major lysosomal proteins in the proposed PPP network regulating glucocerebrosidase (GCase) activity in the lysosome. In this network, (1) CTSD plays a major role in prosaposin (PSAP) cleavage; (2) PSAP is essential for GCase activation and progranulin (PGRN) transport; and (3) PGRN modulates PSAP trafficking and CTSD maturation, 25 as well as levels of lysosomal bis(monoacylglycerol)phosphate, a positive regulator of GCase 26 . Alterations to this network would impact GCase activity, resulting in glycosphingolipid accumulation.…”

Section: Figurementioning

confidence: 99%

CRISPR/Cas9‐Based Functional Genomics in Human Induced Pluripotent Stem Cell–Derived Models: Can “the Stars Align” for Neurodegenerative Diseases?

et al. 2022

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Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

Cited by 141 publications

References 76 publications

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Progranulin deficiency results in reduced bis(monoacylglycero)phosphate (BMP) levels and gangliosidosis

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation

CRISPR/Cas9‐Based Functional Genomics in Human Induced Pluripotent Stem Cell–Derived Models: Can “the Stars Align” for Neurodegenerative Diseases?

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