scholarly journals Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases

Brain ◽  
2020 ◽  
Vol 143 (8) ◽  
pp. 2398-2405 ◽  
Author(s):  
Shinsuke Ishigaki ◽  
Yuichi Riku ◽  
Yusuke Fujioka ◽  
Kuniyuki Endo ◽  
Nobuyuki Iwade ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alzheimer Disease ◽  
Progressive Supranuclear Palsy ◽  
Corticobasal Degeneration ◽  
Pick's Disease ◽  
Pick’S Disease ◽  
Subsequent Increase ◽  
Fused In Sarcoma ◽  
Wide Range

Abstract Fused in sarcoma (FUS) is genetically and clinicopathologically linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). We have previously reported that intranuclear interactions of FUS and splicing factor, proline- and glutamine-rich (SFPQ) contribute to neuronal homeostasis. Disruption of the FUS-SFPQ interaction leads to an increase in the ratio of 4-repeat tau (4R-tau)/3-repeat tau (3R-tau), which manifests in FTLD-like phenotypes in mice. Here, we examined FUS-SFPQ interactions in 142 autopsied individuals with FUS-related ALS/FTLD (ALS/FTLD-FUS), TDP-43-related ALS/FTLD (ALS/FTLD-TDP), progressive supranuclear palsy, corticobasal degeneration, Alzheimer’s disease, or Pick’s disease as well as controls. Immunofluorescent imaging showed impaired intranuclear co-localization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, progressive supranuclear palsy and corticobasal degeneration cases, but not in Alzheimer’s disease or Pick’s disease cases. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and progressive supranuclear palsy cases, but not in those with Alzheimer disease. Furthermore, the ratio of 4R/3R-tau was elevated in cases with ALS/FTLD-TDP and progressive supranuclear palsy, but was largely unaffected in cases with Alzheimer disease. We concluded that impaired interactions between intranuclear FUS and SFPQ and the subsequent increase in the ratio of 4R/3R-tau constitute a common pathogenesis pathway in FTLD spectrum diseases.

scholarly journals Novel tau filament fold in corticobasal degeneration, a four-repeat tauopathy

2019 ◽  
Author(s):  
Wenjuan Zhang ◽  
Airi Tarutani ◽  
Kathy L. Newell ◽  
Alexey G. Murzin ◽  
Tomoyasu Matsubara ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Chronic Traumatic Encephalopathy ◽  
Association Studies ◽  
Corticobasal Degeneration ◽  
Pick's Disease ◽  
Genome Wide Association Studies ◽  
Pick’S Disease ◽  
Tau Isoforms ◽  
Cognitive Disturbances

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy that is characterised by motor and cognitive disturbances (1–3). A higher frequency of the H1 haplotype of MAPT, the tau gene, is present in cases of CBD than in controls (4, 5) and genome-wide association studies have identified additional risk factors (6). By histology, astrocytic plaques are diagnostic of CBD (7, 8), as are detergent-insoluble tau fragments of 37 kDa by SDS-PAGE (9). Like progressive supranuclear palsy (PSP), globular glial tauopathy (GGT) and argyrophilic grain disease (AGD) (10), CBD is characterised by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats (4R) (11–15). This distinguishes 4R tauopathies from Pick’s disease, filaments of which are made of three-repeat (3R) tau isoforms, and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE), where both 3R and 4R tau isoforms are found in the filaments (16). Here we report the structures of tau filaments extracted from the brains of three individuals with CBD using electron cryo-microscopy (cryo-EM). They were identical between cases, but distinct from those of Alzheimer’s disease, Pick’s disease and CTE (17–19). The core of CBD filaments comprises residues K274-E380 of tau, spanning the last residue of R1, the whole of R2, R3 and R4, as well as 12 amino acids after R4. It adopts a novel four-layered fold, which encloses a large non-proteinaceous density. The latter is surrounded by the side chains of lysine residues 290 and 294 from R2 and 370 from the sequence after R4. CBD is the first 4R tauopathy with filaments of known structure.

Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms

Brain ◽  
2021 ◽  
Author(s):  
Masato Hosokawa ◽  
Masami Masuda-Suzukake ◽  
Hiroshi Shitara ◽  
Aki Shimozawa ◽  
Genjiro Suzuki ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Corticobasal Degeneration ◽  
Pick's Disease ◽  
Intracerebral Injection ◽  
Pick’S Disease ◽  
Species Barrier ◽  
Alternative Mrna Splicing ◽  
Tau Isoforms

Abstract The phenomenon of "prion-like propagation" in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein of tau contains a microtubule-binding domain which consists of 3-repeats or 4-repeats due to alternative mRNA splicing of transcripts for the Microtubule-associated protein of tau gene. Although a number of models for tau propagation have been reported, most utilize 4-repeat human tau transgenic mice or adult wild-type mice expressing only endogenous 4-repeat tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3-repeat and 4-repeat tau accumulate simultaneously, or that of Pick’s disease in which only 3-repeat tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3-repeat and 4-repeat tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer’s disease (3- and 4-repeat tauopathy), corticobasal degeneration (4-repeat tauopathy) or Pick’s disease (3-repeat tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3- and 4-repeat tau in Alzheimer’s disease-injected brains, 4-repeat tau only in corticobasal degeneration-injected brains, and 3-repeat tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick’s body-like inclusions were observed in Pick’s disease-injected mice, and accumulations characteristic of Pick’s disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick’s disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3- and 4-repeat-isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.

A Study on the Symptomatology and Differential Diagnosis of Alzheimer's Disease and Pick's Disease

1943 ◽  
Vol 89 (374) ◽  
pp. 1-20 ◽  
Author(s):  
E. Stengel
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Differential Diagnosis ◽  
Mental Hospital ◽  
Senile Dementia ◽  
Clinical Entity ◽  
Mental Condition ◽  
Pick's Disease ◽  
Pick’S Disease ◽  
Vascular Origin

Many problems concerning Alzheimer's disease and Pick's disease are still awaiting clarification. In this country Henderson was the first to draw attention to the considerable importance of Alzheimer's disease in clinical psychiatry. Valuable work has been contributed by various writers in recent years (Grunthal, 1936; Critchley, 1929, 1930, 1931, 1938; Schottky, 1932; Thorpe, 1932; Rothschild, 1934; Malamud, Lowenberg and co-workers, 1929; Mayer-Gross, 1938; Kasanin and Crank, 1933; Jervis and Soltz, 1936; McMenemy, a.o., 1939). While Pick's disease has retained its position as a clinical entity based mainly on the characteristic anatomical picture, the position of Alzheimer's disease in the system of psychiatry has become more complicated; for instance atypical cases have been described presenting the anatomical characters of Alzheimer's disease, though not fitting into the original clinical conception of that disease. Lowenberg and his co-workers (1929) are inclined to regard Alzheimer's disease as a syndrome rather than a clinical entity. Many contributors have directed their main interest to the pathological changes. The knowledge of the symptomatology of those conditions is still incomplete. Further intensive study may enable us not only to base the diagnosis and differential diagnosis of Alzheimer's disease and Pick's disease on more solid clinical knowledge than hitherto, but also to recognize the early stages of those diseases before advancing cerebral degeneration effaces their characteristic clinical features. Unfortunately, most of the cases come under the observation of the psychiatrist only in the later stages of their illness, and it seems that the comparatively small proportion of the mental hospital population they represent does not reflect the incidence of those diseases. It is very likely that many patients die from intercurrent illnesses before their mental condition is recognized or sufficiently advanced to make admission to a mental hospital necessary. The differential diagnosis of those conditions offers considerable difficulties which often may prove insuperable. Alzheimer's disease and Pick's disease have to be distinguished not only from each other but from conditions of vascular origin, from senile dementia and various atypical conditions which occur at the same age period during which Alzheimer's disease and Pick's disease usually develop. Only careful collection and analysis of clinical observations and their scrutiny by pathological investigations can increase our still limited knowledge in this important field of psychiatry.

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