Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Progranulin gene polymorphisms are linked to Alzheimer's disease (AD) and complete loss of function causes neuronal ceroid lipofuscinosis.
|
30696728 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models.
|
30559071 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Because homozygous mutations in MFSD8 cause neuronal ceroid lipofuscinosis (NCL), similar to homozygous mutations in GRN, we assessed rare variants in MFSD8 for relevance to FTLD through experimental follow-up studies.
|
30382371 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Collectively, our results provide new understanding on PGRN trafficking and shed light on the molecular mechanisms behind FTLD and NCL caused by PGRN mutations.
|
26370502 |
2015 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice.
|
28647554 |
2017 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Furthermore, the strongest evidence for lysosomal impairment in FTD is provided by the progranulin (GRN) gene, which is linked to FTD and neuronal ceroid lipofuscinosis.
|
27166223 |
2016 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Here, we address these issues using an AAV vector (AAV-<i>Grn</i>) to deliver progranulin in <i>Grn</i><sup>-/-</sup> mice (both male and female), which model aspects of NCL and FTD pathology, developing lysosomal dysfunction, lipofuscinosis, and microgliosis.
|
29378861 |
2018 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Homozygous GRN mutation carriers develop neuronal ceroid lipofuscinosis (NCL), an earlier-onset lysosomal storage disorder caused by severe lysosomal dysfunction.
|
29929528 |
2018 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
However, growing evidence suggests a role for PGRN in the lysosome-most striking being that homozygous GRN mutation leads to neuronal ceroid lipofuscinosis, a lysosomal storage disease.
|
29744576 |
2018 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
AlteredExpression
|
disease |
BEFREE |
However, the primary mechanism that causes impaired protein degradation and elevated CatD levels upon PGRN deficiency in NCL and FTLD remains unclear.
|
30180904 |
2018 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
AlteredExpression
|
disease |
BEFREE |
In line with a potential pathological overlap of FTLD and NCL, Ctsd(-/-) mice, a model for NCL, show elevated levels of the FTLD-associated proteins GRN and TMEM106B.
|
24619111 |
2014 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
AlteredExpression
|
disease |
BEFREE |
In this study, we evaluated whether selective depletion of progranulin expression in myeloid-lineage cells, including microglia, causes NCL-like neuropathology or neuroinflammation in mice.
|
29149899 |
2017 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Individuals with loss-of-function mutations on both GRN alleles develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder.
|
30448285 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL).
|
31291241 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Mutations in the GRN gene can lead to frontotemporal lobar degeneration (FTLD), a cause of dementia, and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease.
|
30862089 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
NCL type 11 was first described in 2014 in two siblings as adult-onset NCL and was found to be due to a homozygous progranulin gene mutation.
|
30922528 |
2019 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in <i>GRN</i>-associated FTD and <i>GRN</i>-associated NCL.
|
28404863 |
2017 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Progranulin (PGRN) haploinsufficiency resulting from loss-of-function mutations in the PGRN gene causes frontotemporal lobar degeneration accompanied by TDP-43 accumulation, and patients with homozygous mutations in the PGRN gene present with neuronal ceroid lipofuscinosis.
|
28073925 |
2017 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Recently, homozygous GRN mutations were detected in two patients with neuronal ceroid lipofuscinosis, a lysosomal storage disease.
|
22859297 |
2012 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease.
|
28743268 |
2017 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
GeneticVariation
|
disease |
BEFREE |
Recurrent generalized seizures, visual loss, and palinopsia as phenotypic features of neuronal ceroid lipofuscinosis due to progranulin gene mutation.
|
24779634 |
2014 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL.
|
22608501 |
2012 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
The present study shows that aged PGRN-deficient mice present with NCL-like pathology as well as TDP-43 aggregates in the VPM/VPL, where a particular vulnerability has been reported in NCL model mice.
|
25022663 |
2014 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
This functional relationship between PGRN and cathepsin D provides a possible explanation for overlapping NCL-like pathology observed in patients with mutations in PGRN or CTSD, the gene encoding cathepsin D. Together, our work identifies PGRN as an activator of lysosomal cathepsin D activity, and suggests that decreased cathepsin D activity due to loss of PGRN contributes to both FTD and NCL pathology in a dose-dependent manner.
|
29036611 |
2017 |
Neuronal Ceroid-Lipofuscinoses
|
0.100 |
Biomarker
|
disease |
BEFREE |
Thus, our data demonstrate a role of PGRN in PSAP lysosomal trafficking and suggest that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations.
|
28541286 |
2017 |