Редактирование: C9orf72

Guanine nucleotide exchange C9orf72

==Publications==

{{medline-entry
|title=Carriership of two copies of [[C9orf72]] hexanucleotide repeat intermediate-length alleles is a risk factor for ALS in the Finnish population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33168078
|abstract=The hexanucleotide repeat expansion in intron 1 of the [[C9orf72]] gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. In addition to the effects of the pathogenic expansion, a role of intermediate-length alleles has been suggested in ALS, corticobasal degeneration and Parkinson's disease. Due to the rarity of intermediate-length alleles with over 20 repeats and the geographical variability in their frequency, large studies that account for population stratification are needed to elucidate their effects. To this aim, we used repeat-primed PCR and confirmatory PCR assays to determine the [[C9orf72]] repeat allele lengths in 705 ALS patients and 3958 controls from Finland. After exclusion of expansion carriers (25.5% of the ALS patients and 0.2% of the controls), we compared the frequency of intermediate-length allele carriers of 525 ALS cases and 3950 controls using several intermediate-length allele thresholds (7-45, 17-45, 21-45, 24-45 and 24-30). The carriership of an intermediate-length allele did not associate with ALS (Fisher's test, all p ≥ 0.15) nor was there any association with survival (p ≥ 0.33), when we divided our control group into three age groups (18-65, 66-84 and 85-105 years). Carriership of two intermediate-length alleles was associated with ALS, when the longer allele was ≥ 17 repeats (p = 0.002, OR 5.32 95% CI 2.02-14.05) or ≥ 21 repeats (p = 0.00016, OR 15.21 95% CI 3.79-61.0). Our results show that intermediate-length alleles are a risk factor of ALS when present in both alleles, whereas carrying just one intermediate-length allele was not associated with ALS or survival.

|keywords=* ALS
* Aging
* C9orf72
* Case-control analysis
* Intermediate repeats
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654028
}}
{{medline-entry
|title=Deregulated expression of a longevity gene, Klotho, in the [[C9orf72]] deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32887666
|abstract=Hexanucleotide repeat expansion of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Synergies between loss of C9ORF72 functions and gain of toxicities from the repeat expansions contribute to C9ORF72-mediated pathogenesis. However, how loss of [[C9orf72]] impacts neuronal and synaptic functions remains undetermined. Here, we showed that long-term potentiation at the dentate granule cells and long-term depression at the Schaffer collateral/commissural synapses at the area [[CA1]] were reduced in the hippocampus of [[C9orf72]] knockout mice. Using unbiased transcriptomic analysis, we identified that Klotho, a longevity gene, was selectively dysregulated in an age-dependent manner. Specifically, Klotho protein expression in the hippocampus of [[C9orf72]] knockout mice was incorrectly enriched in the dendritic regions of [[CA1]] with concomitant reduction in granule cell layer of dentate gyrus at 3-month of age followed by an accelerating decline during aging. Furthermore, adult hippocampal neurogenesis was reduced in [[C9orf72]] knockout mice. Taken together, our data suggest that C9ORF72 is required for synaptic plasticity and adult neurogenesis in the hippocampus and Klotho deregulations may be part of C9ORF72-mediated toxicity.

|keywords=* Amyotrophic lateral sclerosis (ALS)
* C9ORF72
* Dentate gyrus, adult neurogenesis
* Frontotemporal dementia (FTD)
* Klotho
* Long-term depression (LTD)
* Long-term potentiation (LTP)
* Longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473815
}}
{{medline-entry
|title=[[C9]]orf72 in myeloid cells suppresses STING-induced inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32814898
|abstract=Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation . Expansions of a hexanucleotide repeat (GGGGCC) in the [[C9]]orf72 gene are the most common cause of familial ALS and FTD ([[C9]]-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased [[C9]]orf72 protein expression in brain and peripheral blood cells . Here we show in mice that loss of [[C9]]orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of [[C9]]orf72. Dendritic cells isolated from [[C9]]orf72  mice show marked early activation of the type I interferon response, and [[C9]]orf72  myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in [[C9]]orf72  myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in [[C9]]orf72  immune cells as well as splenomegaly and inflammation in [[C9]]orf72  mice. Moreover, mice lacking one or both copies of [[C9]]orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with [[C9]]-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with [[C9]]-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with [[C9]]-ALS/FTD have an altered immunophenotype because their reduced levels of [[C9]]orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.
|mesh-terms=* Aging
* Amyotrophic Lateral Sclerosis
* Animals
* C9orf72 Protein
* Dendritic Cells
* Encephalomyelitis, Autoimmune, Experimental
* Female
* Humans
* Inflammation
* Interferon Type I
* Membrane Proteins
* Mice
* Myeloid Cells
* Neoplasms
* T-Lymphocytes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484469
}}
{{medline-entry
|title=Glycine-alanine dipeptide repeats spread rapidly in a repeat length- and age-dependent manner in the fly brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31843021
|abstract=Hexanucleotide repeat expansions of variable size in [[C9]]orf72 are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense transcripts of the expansions are translated by repeat-associated non-AUG translation into five dipeptide repeat proteins (DPRs). Of these, the polyGR, polyPR and, to a lesser extent, polyGA DPRs are neurotoxic, with polyGA the most abundantly detected DPR in patient tissue. Trans-cellular transmission of protein aggregates has recently emerged as a major driver of toxicity in various neurodegenerative diseases. In vitro evidence suggests that the [[C9]] DPRs can spread. However, whether this phenomenon occurs under more complex in vivo conditions remains unexplored. Here, we used the adult fly brain to investigate whether the [[C9]] DPRs can spread in vivo upon expression in a subset of neurons. We found that only polyGA can progressively spread throughout the brain, which accumulates in the shape of aggregate-like puncta inside recipient cells. Interestingly, GA transmission occurred as early as 3 days after expression induction. By comparing the spread of 36, 100 and 200 polyGA repeats, we found that polyGA spread is enhanced upon expression of longer GA DPRs. Transmission of polyGA is greater in older flies, indicating that age-associated factors exacerbate the spread. These data highlight a unique propensity of polyGA to spread throughout the brain, which could contribute to the greater abundance of polyGA in patient tissue. In addition, we present a model of early GA transmission that is suitable for genetic screens to identify mechanisms of spread and its consequences in vivo.
|mesh-terms=* Aging
* Alanine
* Animals
* Animals, Genetically Modified
* Brain
* C9orf72 Protein
* DNA Repeat Expansion
* Dipeptides
* Drosophila
* Female
* Glycine
|keywords=* Ageing
* C9orf72
* Dipeptide repeat proteins
* Drosophila
* PolyGA
* Repeat size
* Spread
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916080
}}
{{medline-entry
|title=Human iPSC-derived astrocytes from ALS patients with mutated [[C9]]ORF72 show increased oxidative stress and neurotoxicity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31787569
|abstract=Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons (MNs). It was shown that human astrocytes with mutations in genes associated with ALS, like [[C9]]orf72 ([[C9]]) or [[SOD1]], reduce survival of MNs. Astrocyte toxicity may be related to their dysfunction or the release of neurotoxic factors. We used human induced pluripotent stem cell-derived astrocytes from ALS patients carrying [[C9]]orf72 mutations and non-affected donors. We utilized these cells to investigate astrocytic induced neuronal toxicity, changes in astrocyte transcription profile as well as changes in secretome profiles. We report that [[C9]]-mutated astrocytes are toxic to MNs via soluble factors. The toxic effects of astrocytes are positively correlated with the length of astrocyte propagation in culture, consistent with the age-related nature of ALS. We show that [[C9]]-mutated astrocytes downregulate the secretion of several antioxidant proteins. In line with these findings, we show increased astrocytic oxidative stress and senescence. Importantly, media conditioned by [[C9]]-astrocytes increased oxidative stress in wild type MNs. Our results suggest that dysfunction of [[C9]]-astrocytes leads to oxidative stress of themselves and MNs, which probably contributes to neurodegeneration. Our findings suggest that therapeutic strategies in familial ALS must not only target MNs but also focus on astrocytes to abrogate nervous system injury.
|mesh-terms=* Amyotrophic Lateral Sclerosis
* Animals
* Astrocytes
* Biomarkers
* C9orf72 Protein
* Cells, Cultured
* Cellular Reprogramming
* Cellular Senescence
* Cerebral Cortex
* Disease Models, Animal
* Gene Expression Profiling
* Glutamic Acid
* Humans
* Induced Pluripotent Stem Cells
* Mice
* Motor Neurons
* Mutation
* Oxidative Stress
* Proteomics
* Reactive Oxygen Species
|keywords=* Amyotrophic lateral sclerosis
* Astrocytes
* Neurotoxicity
* Oxidative stress
* Senescence
* iPSC
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921360
}}
{{medline-entry
|title=[[C9]]orf72 Dipeptide Repeats Cause Selective Neurodegeneration and Cell-Autonomous Excitotoxicity in [i]Drosophila[/i] Glutamatergic Neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30037833
|abstract=The arginine-rich dipeptide repeats (DPRs) are highly toxic products from the [[C9]]orf72 repeat expansion mutations, which are the most common causes of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the effects of DPRs in the synaptic regulation and excitotoxicity remain elusive, and how they contribute to the development of FTD is primarily unknown. By expressing DPRs with different toxicity strength in various neuronal populations in a [i]Drosophila[/i] model, we unexpectedly found that Glycine-Arginine/Proline-Arginine (GR/PR) with 36 repeats could lead to neurodegenerative phenotypes only when they were expressed in glutamatergic neurons, including motor neurons. We detected increased extracellular glutamate and intracellular calcium levels in GR/PR-expressing larval ventral nerve cord and/or adult brain, accompanied by significant increase of synaptic boutons and active zones in larval neuromuscular junctions. Inhibiting the vesicular glutamate transporter expression or blocking the NMDA receptor in presynaptic glutamatergic motor neurons could effectively rescue the motor deficits and shortened life span caused by poly GR/PR, thus indicating a cell-autonomous excitotoxicity mechanism. Therefore, our results have revealed a novel mode of synaptic regulation by arginine-rich [[C9]] DPRs expressed at more physiologically relevant toxicity levels and provided a mechanism that could contribute to the development of [[C9]]-related ALS and FTD.  [[C9]]orf72 dipeptide repeats (DPRs) are key toxic species causing ALS/FTD, but their roles in synaptic regulation and excitotoxicity are unclear. Using [[C9]]orf72 DPRs with various toxicity strength, we have found that the arginine-rich DPRs cause selective degeneration in [i]Drosophila[/i] glutamatergic neurons and revealed an NMDA receptor-dependent cell-autonomous excitotoxicity mechanism. Therefore, this study has advanced our understanding of [[C9]]orf72 DPR functions in synaptic regulation and excitotoxicity and provided a new mechanism that could contribute to the development of [[C9]]-related ALS and FTD.
|mesh-terms=* Animals
* Animals, Genetically Modified
* Arginine
* C9orf72 Protein
* Dipeptides
* Drosophila Proteins
* Drosophila melanogaster
* Genes, Reporter
* Glutamic Acid
* Glycine
* Larva
* Longevity
* Male
* Minisatellite Repeats
* Motor Activity
* Motor Neurons
* Nerve Degeneration
* Neurons
* Proline
* Vesicular Glutamate Transport Proteins
|keywords=* ALS
* C9orf72 dipeptide repeats
* FTD
* cell-autonomous
* excitotoxicity
* selective neurotoxicity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705968
}}
{{medline-entry
|title=Age-related penetrance of the [[C9orf72]] repeat expansion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28522837
|abstract=A pathogenic hexanucleotide repeat expansion within the [[C9orf72]] gene has been identified as the major cause of two neurodegenerative syndromes, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This mutation is known to have incomplete penetrance, with some patients developing disease in their twenties and a small portion of carriers surviving to their ninth decade without developing symptoms. Describing penetrance by age among [[C9orf72]] carriers and identifying parameters that alter onset age are essential to better understanding this locus and to enhance predictive counseling. To do so, data from 1,170 individuals were used to model penetrance. Our analysis showed that the penetrance was incomplete and age-dependent. Additionally, familial and sporadic penetrance did not significantly differ from one another; ALS cases exhibited earlier age of onset than FTD cases; and individuals with spinal-onset exhibited earlier age of onset than those with bulbar-onset. The older age of onset among female cases in general, and among female bulbar-onset cases in particular, was the most striking finding, and there may be an environmental, lifestyle, or hormonal factor that is influencing these penetrance patterns. These results will have important applications for future clinical research, the identification of disease modifiers, and genetic counseling.
|mesh-terms=* Adolescent
* Adult
* Age of Onset
* Aged
* Aging
* Amyotrophic Lateral Sclerosis
* C9orf72 Protein
* Child
* Child, Preschool
* DNA Repeat Expansion
* Female
* Frontotemporal Dementia
* Humans
* Infant
* Male
* Middle Aged
* Penetrance

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437033
}}
{{medline-entry
|title=DNA methylation age-acceleration is associated with disease duration and age at onset in [[C9orf72]] patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/28439722
|abstract=The repeat expansion in [[C9orf72]] is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. [[C9orf72]] patients present with a wide range in disease duration and age of onset. The strongest risk factor for both syndromes is aging, which was linked to DNA methylation (DNAm) age based on the cumulative assessment of the methylation levels of 353 CpGs included on the genome-wide 450k BeadChip. DNAm age may reflect biological age better than chronological age. We conducted a genome-wide blood DNA methylation study of 46 unrelated [[C9orf72]] patients. After correction for multiple testing, none of the CpGs demonstrated association between its methylation level and disease duration or age of onset. However, we detected a significant reverse correlation of DNAm age-acceleration with disease duration and age of onset, suggesting that for every 5-year increase in DNAm age-acceleration there is a 3.2-year earlier age of onset and 1.5-year shorter disease duration. The significant correlations remain after adjusting for gender, [[TMEM106B]] genotypes, disease phenotype and [[C9orf72]] 5'CpG island methylation status. A similar trend was observed for the blood DNA of affected members of an extended [[C9orf72]] family; and tissues from the central nervous system of [[C9orf72]] autopsy cases. For instance, regression analysis suggested that a 5-year increase in DNAm age-acceleration is linked to an earlier age of onset by 4.7 or 5.5 years for frontal cortex or spinal cord, respectively. Blood DNAm age may be a useful biomarker for biological age, because blood DNAm age-acceleration was similar to all investigated brain tissues, except for cerebellum that ages more slowly. In conclusion, DNA methylation analysis of [[C9orf72]] patients revealed that increased DNAm age-acceleration is associated with a more severe disease phenotype with a shorter disease duration and earlier age of onset.
|mesh-terms=* Age of Onset
* Aged
* Aged, 80 and over
* Aging
* Amyotrophic Lateral Sclerosis
* C9orf72 Protein
* Central Nervous System
* DNA Methylation
* DNA Repeat Expansion
* Family Health
* Female
* Frontotemporal Dementia
* Genetic Testing
* Humans
* Male
* Middle Aged
|keywords=* ALS
* C9orf72
* DNA methylation age
* FTD
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508035
}}
{{medline-entry
|title=[[C9orf72]] is required for proper macrophage and microglial function in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26989253
|abstract=Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the [[C9orf72]] gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of [[C9orf72]] is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the [[C9orf72]] ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, [[C9orf72]] null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. [[C9orf72]] expression was highest in myeloid cells, and the loss of [[C9orf72]] led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to [[C9orf72]] ALS but not sporadic ALS human patient tissue. Thus, [[C9orf72]] is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in [[C9orf72]] expansion carriers. 
|mesh-terms=* Aging
* Amyotrophic Lateral Sclerosis
* Animals
* C9orf72 Protein
* Frontotemporal Dementia
* Gene Knockdown Techniques
* Guanine Nucleotide Exchange Factors
* Heterozygote
* Humans
* Lymphatic Diseases
* Macrophages
* Mice
* Mice, Knockout
* Microglia
* Myeloid Cells
* Proteins
* Rats
* Splenomegaly

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120541
}}
{{medline-entry
|title=Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26919046
|abstract=Mutations in superoxide dismutase-1 ([[SOD1]]) are a common known cause of amyotrophic lateral sclerosis (ALS). The neurotoxicity of mutant [[SOD1]]s is most likely caused by misfolded molecular species, but disease pathogenesis is still not understood. Proposed mechanisms include impaired mitochondrial function, induction of endoplasmic reticulum stress, reduction in the activities of the proteasome and autophagy, and the formation of neurotoxic aggregates. Here we examined whether perturbations in these cellular pathways in turn influence levels of misfolded [[SOD1]] species, potentially amplifying neurotoxicity. For the study we used fibroblasts, which express [[SOD1]] at physiological levels under regulation of the native promoter. The cells were derived from ALS patients expressing 9 different [[SOD1]] mutants of widely variable molecular characteristics, as well as from patients carrying the GGGGCC-repeat-expansion in [[C9orf72]] and from non-disease controls. A specific ELISA was used to quantify soluble, misfolded [[SOD1]], and aggregated [[SOD1]] was analysed by western blotting. Misfolded [[SOD1]] was detected in all lines. Levels were found to be much lower in non-disease control and the non-[[SOD1]] [[C9orf72]] ALS lines. This enabled us to validate patient fibroblasts for use in subsequent perturbation studies. Mitochondrial inhibition, endoplasmic reticulum stress or autophagy inhibition did not affect soluble misfolded [[SOD1]] and in most cases, detergent-resistant [[SOD1]] aggregates were not detected. However, proteasome inhibition led to uniformly large increases in misfolded [[SOD1]] levels in all cell lines and an increase in [[SOD1]] aggregation in some. Thus the ubiquitin-proteasome pathway is a principal determinant of misfolded [[SOD1]] levels in cells derived both from patients and controls and a decline in activity with aging could be one of the factors behind the mid-to late-life onset of inherited ALS. 
|mesh-terms=* Adenine
* Age of Onset
* Aging
* Amyotrophic Lateral Sclerosis
* Autophagy
* Bortezomib
* C9orf72 Protein
* Case-Control Studies
* Cells, Cultured
* DNA Repeat Expansion
* Electron Transport Complex I
* Endoplasmic Reticulum Stress
* Enzyme-Linked Immunosorbent Assay
* Fibroblasts
* Genotype
* Humans
* Mutation
* Protease Inhibitors
* Proteasome Endopeptidase Complex
* Protein Aggregation, Pathological
* Protein Folding
* Proteins
* Proteolysis
* Rotenone
* Solubility
* Superoxide Dismutase
* Superoxide Dismutase-1

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4769150
}}
{{medline-entry
|title=Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/26912063
|abstract=In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes ([[MAPT]], [[GRN]], [[CHMP2B]], [[CTSC]], [[HLA-DRA]], [[TMEM106B]], [[C9orf72]], [[VCP]], [[UBQLN2]], [[OPTN]], [[TARDBP]] and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. Gene co-expression networks revealed that several FTD-genes (such as [[MAPT]] and [[GRN]], [[CTSC]] and [[HLA-DRA]], [[TMEM106B]], and [[C9orf72]], [[VCP]], [[UBQLN2]] and [[OPTN]]) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling ([[MAPT]] and [[GRN]] modules); ii) immune and lysosomal processes ([[CTSC]] and [[HLA-DRA]] modules), and; iii) protein meta/catabolism ([[C9orf72]], [[VCP]], [[UBQLN2]] and [[OPTN]], and [[TMEM106B]] modules). PPI analysis supported the results of the functional annotation and pathway analyses. This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work.
|mesh-terms=* Aging
* Animals
* Brain Mapping
* Frontotemporal Dementia
* Gene Regulatory Networks
* Genetic Predisposition to Disease
* Intercellular Signaling Peptides and Proteins
* Mutation
* Risk Factors
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4765225
}}