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

2021 ◽  
Author(s):  
Sebastian Boland ◽  
Sharan Swarup ◽  
Yohannes A Ambaw ◽  
Ruth C Richards ◽  
Alexander W Fischer ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Frontotemporal Dementia ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Human Cells ◽  
Lipid Degradation ◽  
Major Function ◽  
Neurodevelopmental Disease ◽  
Homozygous Mutations ◽  
Intensive Investigation ◽  
Human Brains

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.

scholarly journals AAV-mediated progranulin delivery to a mouse model of progranulin deficiency causes T cell-mediated hippocampal degeneration

2018 ◽  
Author(s):  
Defne A. Amado ◽  
Julianne M. Rieders ◽  
Fortunay Diatta ◽  
Pilar Hernandez-Con ◽  
Adina Singer ◽  
...  
Keyword(s):  
T Cell ◽  
Frontotemporal Dementia ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Gene Replacement ◽  
Cell Infiltration ◽  
Great Promise ◽  
Wild Type ◽  
Gene Therapies ◽  
Ceroid Lipofuscinosis ◽  
T Cell Infiltration

AbstractAdeno-associated virus (AAV)-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations, and use of AAV vectors for treatment of diseases of the CNS is increasing. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL), and two recent studies using focal intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse FTD models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that despite a global increase in progranulin throughout many brain regions, overexpression of GRN resulted in dramatic and selective hippocampal toxicity and degeneration affecting both neurons and glia. Histologically, hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing, suggesting an inflammatory component to the ensuing neuronal loss. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid (CSF) similarly resulted in T cell infiltration as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response following GRN gene delivery. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression in relevant animal models prior to progressing to the clinic.Significance StatementGene therapies using adeno-associated viral (AAV) vectors show great promise for many human diseases, including diseases that affect the central nervous system (CNS). Frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL) are neurodegenerative diseases resulting from loss of one or both copies of the gene encoding progranulin (GRN), and gene replacement has been proposed for these currently untreatable disorders. Here, we used two different AAV vectors to induce widespread brain GRN expression in mice lacking the gene, as well as in wild-type mice. Unexpectedly, GRN overexpression resulted in T cell infiltration, followed by marked hippocampal neurodegeneration. Our results call into question the safety of GRN overexpression in the CNS, with wider implications for development of CNS gene therapies.

Novel Mutations in CLN5 of Chinese Patients With Neuronal Ceroid Lipofuscinosis

2018 ◽  
Vol 33 (13) ◽  
pp. 837-850 ◽  
Author(s):  
Lv Ge ◽  
Han Yun Li ◽  
Yuan Hai ◽  
Liu Min ◽  
Li Xing ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Hereditary Disease ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Neuronal Protein ◽  
Ceroid Lipofuscinosis ◽  
Visual Problems ◽  
Homozygous Mutations

Neuronal ceroid lipofuscinosis is a hereditary disease, and ceroid-lipofuscinosis neuronal protein 5 (CLN5) has been proved to be associated with neuronal ceroid lipofuscinosis. Here we report 3 patients from 2 families diagnosed with CLN5 neuronal ceroid lipofuscinosis. Whole genome sequencing of DNAs from 3 patients and their families revealed 3 novel homozygous mutations, including 1 deletion CLN5.c718 719delAT and 2 missense mutations c.1082T>C and c.623G>A. We reviewed 278 papers about neuronal ceroid lipofuscinosis resulting from CLN5 mutations and compared Chinese cases with 27 European and American cases. The overall age of onset of European and American patients occur mainly at 3 to 6 years (66%, 18/27), 100% (27/27) of patients had psychomotor regression, 99% (26/27) patients presented vision decline, and 70% (19/27) of patients suffered seizures. In China, the age of onset in 3 patients was 5 years, but for 1 patient it was at 17 months. Four Chinese patients presented psychomotor deterioration and seizures; only 1 had visual problems.

scholarly journals Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Andrew E. Arrant ◽  
Jonathan R. Roth ◽  
Nicholas R. Boyle ◽  
Shreya N. Kashyap ◽  
Madelyn Q. Hoffmann ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Posttranslational Modifications ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Inferior Frontal Gyrus ◽  
Lysosomal Storage ◽  
Loss Of Function ◽  
Wild Type ◽  
Metabolizing Enzymes ◽  
Dementia Patients ◽  
The Brain

AbstractLoss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn−/− mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing.

scholarly journals Centromeric transcription maintains centromeric cohesion in human cells

2021 ◽  
Vol 220 (7) ◽  
Author(s):  
Yujue Chen ◽  
Qian Zhang ◽  
Zhen Teng ◽  
Hong Liu
Keyword(s):  
Dna Binding ◽  
Gene Transcription ◽  
Direct Consequence ◽  
Human Cells ◽  
Binding Domain ◽  
Dna Binding Domain ◽  
Major Function ◽  
Krab Domain

Centromeric transcription has been shown to play an important role in centromere functions. However, lack of approaches to specifically manipulate centromeric transcription calls into question that the proposed functions are a direct consequence of centromeric transcription. By monitoring nascent RNAs, we found that several transcriptional inhibitors exhibited distinct, even opposing, efficacies on the suppression of ongoing gene and centromeric transcription in human cells, whereas under the same conditions, total centromeric RNAs were changed to a lesser extent. The inhibitor suppressing ongoing centromeric transcription weakened centromeric cohesion, whereas the inhibitor increasing ongoing centromeric transcription strengthened centromeric cohesion. Furthermore, expression of CENP-B DNA-binding domain or CENP-B knockdown moderately increased centromeric transcription without altering gene transcription; as a result, centromeric cohesion was accordingly strengthened. Targeting of the Kox1-KRAB domain with CENP-B DB to centromeres specifically decreased centromeric transcription and weakened centromeric cohesion. Thus, based on these findings, we propose that a major function of centromeric transcription is to maintain centromeric cohesion in human cells.

scholarly journals Surf4 Promotes Endoplasmic Reticulum Exit of the Lysosomal Prosaposin-Progranulin Complex

2021 ◽  
Author(s):  
S. Devireddy ◽  
S.M. Ferguson
Keyword(s):  
Endoplasmic Reticulum ◽  
Frontotemporal Dementia ◽  
Lysosomal Storage Disease ◽  
Intracellular Trafficking ◽  
Secretory Pathway ◽  
Storage Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage ◽  
Efficient Delivery ◽  
Lysosomal Protein

AbstractProgranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interacts with prosaposin, another lysosomal protein, within the lumen of the endoplasmic reticulum (ER) and that prosaposin is required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates a network of interactions occurring early in the secretory pathway that promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo

2021 ◽  
Vol 221 (2) ◽  
Author(s):  
Swathi Devireddy ◽  
Shawn M. Ferguson
Keyword(s):  
Endoplasmic Reticulum ◽  
Frontotemporal Dementia ◽  
Lysosomal Storage Disease ◽  
Intracellular Trafficking ◽  
Secretory Pathway ◽  
Storage Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage ◽  
Efficient Delivery ◽  
Lysosomal Protein

Progranulin is a lysosomal protein whose haploinsufficiency causes frontotemporal dementia, while homozygous loss of progranulin causes neuronal ceroid lipofuscinosis, a lysosomal storage disease. The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interactions with prosaposin, another lysosomal protein, first occur within the lumen of the endoplasmic reticulum (ER) and are required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII-coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates that a network of interactions occurring early in the secretory pathway promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.

The expression of late infantile neuronal ceroid lipofuscinosis (CLN2) gene product in human brains

1998 ◽  
Vol 257 (2) ◽  
pp. 113-115 ◽  
Author(s):  
Akira Oka ◽  
Yukiko Kurachi ◽  
Masashi Mizuguchi ◽  
Masaharu Hayashi ◽  
Sachio Takashima
Keyword(s):  
Gene Product ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Human Brains

scholarly journals Homozygous GRN mutations: new phenotypes and new insights into pathological and molecular mechanisms

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 303-319 ◽  
Author(s):  
Vincent Huin ◽  
Mathieu Barbier ◽  
Armand Bottani ◽  
Johannes Alexander Lobrinus ◽  
Fabienne Clot ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Cerebellar Ataxia ◽  
Genetic Counselling ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Age At Onset ◽  
Genetic Diagnosis ◽  
Cytoplasmic Inclusions ◽  
Ceroid Lipofuscinosis

Abstract Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counselling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.

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