Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway

Elia, Lisa P.; Mason, Amanda; Alijagic, Amela; Finkbeiner, Steven

doi:10.1523/jneurosci.3498-17.2019

Cited by 47 publications

(49 citation statements)

References 100 publications

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“…To analyze the GRN levels in iNs, we performed ELISA on the culture supernatant [29]. The ELISA revealed higher GRN levels in RedPenMC than AMC, but not statistically significant (fig.7A), which reiterates our CITE-seq finding (described above) that neuronal GRN levels between AMC and RedPenMC are not significantly different.…”

Section: Resultssupporting

confidence: 68%

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Natarajan

Eisfeldt

Hammond

et al. 2020

Preprint

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We identified an individual with reduced penetrance (RedPenMC) associated with an autosomal dominant progranulin (GRN) pathogenic variant (p.Tyr294*) causing frontotemporal dementia. The RedPenMC carrier had no signs or symptoms of frontotemporal lobar degeneration in life or at autopsy. This resistance to develop expected pathology gives a unique opportunity to interrogate neurodegenerative mechanisms, identify protective disease modifiers, and gain new therapeutic insights. We performed multimodal droplet-based single nuclei analyses of the frontal cortex from the RedPenMC post-mortem, including unbiased transcriptomics and profiling of global levels of twelve chromatin marks. Further, we analyzed neurons directly reprogrammed from skin fibroblasts from RedPenMC. Single nuclei analyses revealed that the RedPenMC carrier showed a higher expression of GRN in microglia than in any other cell types as well as compared to an affected mutation carrier and a non-carrier. Global levels of heterochromatin marks H3k9me1 and H3k9me3 were significantly lower in the RedPenMC carrier, whereas global levels of H2A2 were significantly upregulated in the RedPenMC carrier compared to an affected mutation carrier. Analyses of directly reprogrammed neurons from the RedPenMC carrier suggested a dendritic loss of GRN and spillage of TAR DNA-binding protein 43 (TDP-43) from the nucleus into the cytoplasm which was not observed in directly reprogrammed neurons from non-carriers. Taken together, our data suggest that higher expression of GRN in microglia and reduced levels of repressive marks may provide endogenous protection against the disease process/neurodegeneration in the RedPenMC carrier. Our study uses unique patient material and provides novel insights into disease mechanisms that can be explored for designing new therapeutic approaches for GRN associated frontotemporal dementia.

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Section: Resultssupporting

confidence: 68%

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Natarajan

Eisfeldt

Hammond

et al. 2020

Preprint

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“…We selected two human PDAC cell lines, MiaPaCa2 and PaTuT cells, with relatively high PGRN expression levels (Figure S3a-c It was demonstrated that pancreatic cancer cells down-regulated surface MHCI by autophagy-mediated degradation (31). Coincidentally, PGRN was shown to regulate autophagy in various cell types (32,33). PGRN-deficient mice showed defective degradation of autophagosomes under starvation (34), which was mediated by lysosomal enzymes cathepsin D (35).…”

Section: Pgrn Suppression Leads To Surface Mhci Upregulation and Dysfmentioning

confidence: 99%

Progranulin promotes immune evasion of pancreatic adenocarcinoma through regulation of MHCI expression

Cheung

Yang

Krengel

et al. 2021

Preprint

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Immune evasion is indispensable for cancer initiation and progression, although its underlying mechanisms in pancreatic ductal adenocarcinoma (PDAC) remain elusive. Here, we unveiled a cancer cell-autonomous function of PGRN in driving immune evasion in primary PDAC. Tumor- but not macrophage-derived PGRN was associated with poor overall survival in PDAC. Multiplex immunohistochemistry revealed low MHC class I (MHCI) expression and lack of CD8+ T cells infiltration in PGRN-high tumors. Inhibition of PGRN abrogated autophagy-dependent MHCI degradation and restored MHCI expression on PDAC cells. Antibody-based blockade of PGRN in a genetic PDAC mouse model remarkably decelerated tumor initiation and progression. Notably, tumors expressing LCMV-gp33 as model antigen were sensitized towards cytotoxic gp33-TCR transgenic T cells upon anti-PGRN antibody treatment. Overall, our study uncovered an unprecedented role of tumor-derived PGRN in regulating immunogenicity of primary PDAC.

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“…GRN is a gene that encodes progranulin (PGRN) (Holler et al, 2017). PGRN can regulate lysosome function, and PGRN deficiency in neurons increases autophagy and causes abnormally enlarged lysosomes (Elia et al, 2019).…”

Section: Amyotrophic Lateral Sclerosis (Als) and Frontotemporal Demenmentioning

confidence: 99%

Golgi Apparatus: A Potential Therapeutic Target for Autophagy-Associated Neurological Diseases

Deng

Liu

et al. 2020

Front. Cell Dev. Biol.

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Autophagy has dual effects in human diseases: appropriate autophagy may protect cells from stress, while excessive autophagy may cause cell death. Additionally, close interactions exist between autophagy and the Golgi. This review outlines recent advances regarding the role of the Golgi apparatus in autophagy. The signaling processes of autophagy are dependent on the normal function of the Golgi. Specifically, (i) autophagy-related protein 9 is mainly located in the Golgi and forms new autophagosomes in response to stressors; (ii) Golgi fragmentation is induced by Golgirelated proteins and accompanied with autophagy induction; and (iii) the endoplasmic reticulum-Golgi intermediate compartment and the reticular trans-Golgi network play essential roles in autophagosome formation to provide a template for lipidation of microtubule-associated protein 1A/1B-light chain 3 and induce further ubiquitination. Golgi-related proteins regulate formation of autophagosomes, and disrupted formation of autophagy can influence Golgi function. Notably, aberrant autophagy has been demonstrated to be implicated in neurological diseases. Thus, targeted therapies aimed at protecting the Golgi or regulating Golgi proteins might prevent or ameliorate autophagy-related neurological diseases. Further studies are needed to investigate the potential application of Golgi therapy in autophagy-based neurological diseases.

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Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway

Cited by 47 publications

References 100 publications

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Single-cell multimodal omics and directly reprogrammed neurons to probe reduced penetrance in Frontotemporal Dementia

Progranulin promotes immune evasion of pancreatic adenocarcinoma through regulation of MHCI expression

Golgi Apparatus: A Potential Therapeutic Target for Autophagy-Associated Neurological Diseases

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