scholarly journals Network analysis of the brain proteome of GRN knockout mice reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

2020 ◽  
Vol 16 (S3) ◽  
Author(s):  
Thomas Kukar ◽  
Meixiang Huang ◽  
Erica S Modeste ◽  
Eric B Dammer ◽  
Christopher J Holler ◽  
...  
Keyword(s):  
Network Analysis ◽  
Frontotemporal Dementia ◽  
Knockout Mice ◽  
Pathogenic Mechanisms ◽  
Brain Proteome ◽  
The Brain

scholarly journals Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2162
Author(s):  
Karima Schwab ◽  
Valeria Melis ◽  
Charles R. Harrington ◽  
Claude M. Wischik ◽  
Mandy Magbagbeolu ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Stress Responses ◽  
Protein Ubiquitination ◽  
Brain Proteome ◽  
Homeostatic Function ◽  
Behavioural Phenotypes ◽  
Tau Aggregation ◽  
The Brain ◽  
Key Pathways ◽  
Dimensional Electrophoresis

Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and hydromethylthionine treatments of line 66 mice were compared. The brain proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify protein networks and pathways that were altered due to tau overexpression or modified by hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and protein ubiquitination were activated by hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain.

Neurobiology of FTD

2017 ◽  
Author(s):  
Dah-Eun Chloe Chung ◽  
Jeannette N. Stankowski ◽  
Leonard Petrucelli
Keyword(s):  
Frontotemporal Dementia ◽  
Model Systems ◽  
Novel Therapies ◽  
Novel Genes ◽  
Pathogenic Mechanisms ◽  
Temporal Lobes ◽  
The Third ◽  
The Brain

Frontotemporal dementia (FTD) is the third most common form of dementia, and is one that predominantly affects the frontal and temporal lobes. Pathological heterogeneity of FTD is highlighted in various types of protein inclusions in the brain, which can include tau, TDP-43, or FUS. The discovery of novel genes and mutations associated with FTD, along with the exciting advancement of molecular technologies, led to the development of numerous animal- and human-based model systems. These valuable models allow not only for the investigation of pathogenic mechanisms underlying FTD, but also for their utilization as powerful platforms for the screening of novel therapies.

scholarly journals Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Meixiang Huang ◽  
Erica Modeste ◽  
Eric Dammer ◽  
Paola Merino ◽  
Georgia Taylor ◽  
...  
Keyword(s):  
Network Analysis ◽  
Frontotemporal Dementia ◽  
Mouse Brain ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Disease Onset ◽  
Loss Of Function ◽  
Lysosomal Dysfunction ◽  
Brain Proteome ◽  
Galectin 3 ◽  
Lysosomal Proteins

Abstract Heterozygous, loss-of-function mutations in the granulin gene (GRN) encoding progranulin (PGRN) are a common cause of frontotemporal dementia (FTD). Homozygous GRN mutations cause neuronal ceroid lipofuscinosis-11 (CLN11), a lysosome storage disease. PGRN is a secreted glycoprotein that can be proteolytically cleaved into seven bioactive 6 kDa granulins. However, it is unclear how deficiency of PGRN and granulins causes neurodegeneration. To gain insight into the mechanisms of FTD pathogenesis, we utilized Tandem Mass Tag isobaric labeling mass spectrometry to perform an unbiased quantitative proteomic analysis of whole-brain tissue from wild type (Grn+/+) and Grn knockout (Grn−/−) mice at 3- and 19-months of age. At 3-months lysosomal proteins (i.e. Gns, Scarb2, Hexb) are selectively increased indicating lysosomal dysfunction is an early consequence of PGRN deficiency. Additionally, proteins involved in lipid metabolism (Acly, Apoc3, Asah1, Gpld1, Ppt1, and Naaa) are decreased; suggesting lysosomal degradation of lipids may be impaired in the Grn−/− brain. Systems biology using weighted correlation network analysis (WGCNA) of the Grn−/− brain proteome identified 26 modules of highly co-expressed proteins. Three modules strongly correlated to Grn deficiency and were enriched with lysosomal proteins (Gpnmb, CtsD, CtsZ, and Tpp1) and inflammatory proteins (Lgals3, GFAP, CD44, S100a, and C1qa). We find that lysosomal dysregulation is exacerbated with age in the Grn−/− mouse brain leading to neuroinflammation, synaptic loss, and decreased markers of oligodendrocytes, myelin, and neurons. In particular, GPNMB and LGALS3 (galectin-3) were upregulated by microglia and elevated in FTD-GRN brain samples, indicating common pathogenic pathways are dysregulated in human FTD cases and Grn−/− mice. GPNMB levels were significantly increased in the cerebrospinal fluid of FTD-GRN patients, but not in MAPT or C9orf72 carriers, suggesting GPNMB could be a biomarker specific to FTD-GRN to monitor disease onset, progression, and drug response. Our findings support the idea that insufficiency of PGRN and granulins in humans causes neurodegeneration through lysosomal dysfunction, defects in autophagy, and neuroinflammation, which could be targeted to develop effective therapies.

The Limits of Emotion

2018 ◽  
Author(s):  
Joshua May
Keyword(s):  
Moral Judgment ◽  
Frontotemporal Dementia ◽  
Empirical Research ◽  
Emotional Processing ◽  
Moral Cognition ◽  
Moral Norms ◽  
Moral Concepts ◽  
Integral Role ◽  
The Brain

Empirical research apparently suggests that emotions play an integral role in moral judgment. The evidence for sentimentalism is diverse, but it is rather weak and has generally been overblown. There is no evidence that our moral concepts themselves are partly composed of or necessarily dependent on emotions. While the moral/conventional distinction may partly characterize the essence of moral judgment, moral norms needn’t be backed by affect in order to transcend convention. Priming people with incidental emotions like disgust doesn’t make them moralize actions. Finally, moral judgment can only be somewhat impaired by damage to areas of the brain that are generally associated with emotional processing (as in acquired sociopathy and frontotemporal dementia). While psychopaths exhibit both emotional and rational deficits, the latter alone can explain any minor defects in moral cognition.

scholarly journals Sporadic C reutzfeldt– J akob disease subtype‐specific alterations of the brain proteome: Impact on R ab3a recycling

PROTEOMICS ◽  
2012 ◽  
Vol 12 (23-24) ◽  
pp. 3610-3620 ◽  
Author(s):  
Joanna Gawinecka ◽  
Franco Cardone ◽  
Abdul R. Asif ◽  
Angela De Pascalis ◽  
Wiebke M. Wemheuer ◽  
...  
Keyword(s):  
Disease Subtype ◽  
Brain Proteome ◽  
The Brain

scholarly journals Microglial NFκB-TNFα hyperactivation induces obsessive–compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia

2017 ◽  
Vol 114 (19) ◽  
pp. 5029-5034 ◽  
Author(s):  
Grietje Krabbe ◽  
S. Sakura Minami ◽  
Jon I. Etchegaray ◽  
Praveen Taneja ◽  
Biljana Djukic ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Frontotemporal Dementia ◽  
Knockout Mice ◽  
Nuclear Factor Κb ◽  
Medium Spiny Neurons ◽  
Obsessive Compulsive ◽  
Compulsive Disorder ◽  
Spiny Neurons ◽  
Increased Risk ◽  
Excessive Grooming

Frontotemporal dementia (FTD) is the second most common dementia before 65 years of age. Haploinsufficiency in the progranulin (GRN) gene accounts for 10% of all cases of familial FTD. GRN mutation carriers have an increased risk of autoimmune disorders, accompanied by elevated levels of tissue necrosis factor (TNF) α. We examined behavioral alterations related to obsessive–compulsive disorder (OCD) and the role of TNFα and related signaling pathways in FTD patients with GRN mutations and in mice lacking progranulin (PGRN). We found that patients and mice with GRN mutations displayed OCD and self-grooming (an OCD-like behavior in mice), respectively. Furthermore, medium spiny neurons in the nucleus accumbens, an area implicated in development of OCD, display hyperexcitability in PGRN knockout mice. Reducing levels of TNFα in PGRN knockout mice abolished excessive self-grooming and the associated hyperexcitability of medium spiny neurons of the nucleus accumbens. In the brain, PGRN is highly expressed in microglia, which are a major source of TNFα. We therefore deleted PGRN specifically in microglia and found that it was sufficient to induce excessive grooming. Importantly, excessive grooming in these mice was prevented by inactivating nuclear factor κB (NF-κB) in microglia/myeloid cells. Our findings suggest that PGRN deficiency leads to excessive NF-κB activation in microglia and elevated TNFα signaling, which in turn lead to hyperexcitability of medium spiny neurons and OCD-like behavior.

How the Brain Moves the Eyes

2014 ◽  
pp. 1-25
Author(s):  
Shirley H. Wray
Keyword(s):  
Cardiac Surgery ◽  
Eye Movements ◽  
Progressive Supranuclear Palsy ◽  
Disease Progression ◽  
Frontotemporal Dementia ◽  
Smooth Pursuit ◽  
Cortical Areas ◽  
Initial Symptoms ◽  
The Brain ◽  
Symptoms And Signs

discusses the brain’s visual architecture for directing and controlling of eye movements:the striate, frontal and parietal cortical areas; and the eye movements themselves—saccades, smooth pursuit, and vergence. The susceptibility to disorders of these systems is illustrated in four detailed cases that follow disease progression from initial symptoms and signs to diagnosis and treatment. The case studies and video displays include a patient with Pick’s disease (frontotemporal dementia), another with Alzheimer’s dementia, and two examples of rare saccadic syndromes, one a patient with the slow saccade syndrome due to progressive supranuclear palsy and one with selective saccadic palsy following cardiac surgery.

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