Neuronal VCP loss of function recapitulates FTLD-TDP pathology.
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ABSTRACT:
SUBMITTER: Wani A
PROVIDER: S-EPMC8383344 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivated VCP in murine postnatal forebrain neurons (VCP cKO). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulated features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
2021-06-16 | GSE178257 | GEO
Project description:Neuronal VCP loss of function recapitulates FTLD-TDP pathology
| PRJNA738150 | ENA
Project description:Dominant mutations in unrelated genes cause fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and include VCP, which is associated with multisystem proteinopathy (MSP). Conditional inactivation of VCP in postnatal forebrain neurons (VCP cKO) caused cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, TDP-43 inclusions and hyperactivity. Quantitative proteomics and single nuclei RNA sequencing on VCP cKO brains identified synaptogenesis and the unfolded protein response as the most decreased and increased pathways respectively. Conditional expression of a single MSP disease mutation, VCP-R155C, in cortical neurons similarly recapitulated features of VCP inactivation and FTLD-TDP. Comparison of transcriptomic and proteomic datasets from genetically defined FTD patients revealed that profiles from GRN carriers were similar to VCP insufficiency. These data support a deficiency in VCP dependent functions as the pathogenic mechanism of FTLD-TDP and reveal an unexpected pathogenic similarity with progranulin deficiency. Enhancing VCP function may be therapeutic in MSP and related forms of FTLD-TDP.
2021-08-06 | PXD026685 | Pride
Project description:Frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) is a neurodegenerative disease primarily affecting the frontal and/or temporal cortices. However, a growing body of evidence suggests that the cerebellum contributes to biochemical, cognitive, and behavioral changes in FTLD-TDP. To evaluate cerebellar TDP-43 expression and function in FTLD-TDP, we analyzed TDP-43 protein levels and the splicing of a TDP-43 target, STMN2, in the cerebellum of 95 FTLD-TDP cases and 25 non-neurological disease controls. Soluble TDP-43 was decreased in the cerebellum of FTLD-TDP cases but a concomitant increase in insoluble TDP-43 was not seen. Truncated STMN2 transcripts, an indicator of TDP-43 dysfunction, were elevated in the cerebellum of FTLD-TDP cases and inversely associated with TDP-43 levels. Additionally, lower cerebellar TDP-43 associated with a younger age at disease onset. We provide evidence of TDP-43 loss of function in the cerebellum in FTLD-TDP, supporting further investigation into this understudied brain region.
| S-EPMC9310392 | biostudies-literature
Project description:We examined the phosphorylated 43-kDa TAR DNA-binding protein (pTDP-43) inclusions as well as neuronal loss in full-length spinal cords and five selected regions of the central nervous system from 36 patients with amyotrophic lateral sclerosis (ALS) and 10 age-matched normal controls. The most severe neuronal loss and pTDP-43 lesions were seen in lamina IX motor nuclei columns 4, 6, and 8 of lower cervical segments and in columns 9-11 of lumbosacral segments. Severity of pTDP-43 pathology and neuronal loss correlated closely with gray and white matter oligodendroglial involvement and was linked to onset of disease, with severe involvement of columns 4, 6, and 8 of upper extremity onset cases and severe involvement of columns of 9, 10, and 11 in cases with lower extremity onset. Severe TDP-43 lesions and neuronal loss were observed in stage 4 cases and sometimes included Onuf's nucleus. Notably, three cases displayed pTDP-43 aggregates in the midbrain oculomotor nucleus, which we had not seen previously even in cases with advanced (i.e., stage 4) pathology. pTDP-43 aggregates were observed in neurons of Clarke's column in 30.6 % of cases but rarely in the intermediolateral nucleus (IML). Gray matter oligodendroglial pTDP-43 inclusions were present in areas devoid of neuronal pTDP-43 aggregates and neuronal loss. Taken together, our findings indicate that (1) the dorsolateral motor nuclei columns of the cervical and lumbosacral anterior horn may be the earliest foci of pTDP-43 pathology in the spinal cord, (2) gray matter oligodendroglial involvement is an early event in the ALS disease process that possibly heralds subsequent involvement of neurons by pTDP-43 pathology, and (3) in some very advanced cases, there is oculomotor nucleus involvement, which may constitute an additional neuropathological stage (designated here as stage 5) of pTDP-43 pathology in ALS.
| S-EPMC4384652 | biostudies-literature
Project description:ObjectiveTo determine the independent association of the TMEM106B variants with transactive response DNA binding protein 43 (TDP-43) pathology in older persons without frontotemporal lobar degeneration (FTLD) and to explore functional pathways that link the risk variants to the pathology, including a GRN mRNA pathway.MethodsData came from 544 autopsied participants without FTLD in 2 community-based studies of aging. Participants underwent uniform neuropathologic evaluations, including TDP-43 cytoplasmic inclusions. We examined the association of TMEM106B variants with a semiquantitative measure of TDP-43 pathology in a series of regression analysis. We explored potential pathways by leveraging genetic, brain DNA methylation, miRNA, and transcriptomic data collected from this same group of participants.ResultsTDP-43 pathology was identified in 51.7% of the participants. The index single-nucleotide polymorphism (SNP), rs1990622(A), was associated with more advanced TDP-43 pathology. Top hits from fine mapping of the locus were in linkage disequilibrium of the index SNP. The association remained significant after adjustment for other neuropathologies including Alzheimer disease and hippocampal sclerosis (odds ratio = 1.351, 95% confidence interval = 1.068-1.709, p = 0.012). GRN expression was upregulated in rs1990622(AA/AG) carriers, and was associated with more advanced TDP-43 pathology. The TMEM106B variants were associated with lower level of DNA methylation in an active enhancer in GRN.ConclusionsCommon variants in TMEM106B serve as a distinct risk factor for TDP-43 pathology in older persons without FTLD. The role of GRN expression and epigenetic mechanisms associating TMEM106B in the accumulation of TDP-43 in older persons require further study.
| S-EPMC4351662 | biostudies-literature
Project description:The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G4C2 repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G4C2)66 throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G4C2)66 mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.
| S-EPMC4692360 | biostudies-literature
Project description:OBJECTIVE:To investigate the association of TAR DNA-binding protein 43 (TDP-43) pathology with memory, other cognitive domains, and dementia in community-dwelling elders without pathologic diagnoses of Alzheimer disease (AD) or frontotemporal lobar degeneration (FTLD). METHODS:Of 1,058 autopsied participants, 343 (32.4%) did not have pathologic diagnoses of AD or FTLD. Diagnosis of dementia was based on clinical evaluation and cognitive performance tests, which were used to create summary measures of global cognition and of 5 cognitive domains. TDP-43 pathology evaluated in 6 brain regions by immunohistochemistry was converted into a summary measure of TDP-43 severity. RESULTS:Of 343 participants, 135 (39.4%) had TDP-43 pathology with a mean TDP-43 severity score of 0.394 (SD 0.490). TDP-43 inclusions were confined to the amygdala (stage 1) in 43.7% of participants, 40% showed additional involvement of the hippocampus or entorhinal cortex (stages 2), while fewer (16.3%) showed additional TDP-43 pathology in the temporal and frontal cortices (stage 3). Severity of TDP-43 pathology was independently related to lower function in global cognition and episodic and semantic memory while increased odds of dementia was only a trend. When participants with hippocampal sclerosis (HS) were excluded from the models, TDP-43 pathology remained associated with lower episodic memory but relationships with global cognition, semantic memory, and dementia were attenuated. CONCLUSIONS:TDP-43 pathology in elders, without pathologic diagnoses of AD or FTLD, is common and independently associated with lower function in episodic memory, while its associations with global cognitive impairment and dementia are difficult to separate from HS.
| S-EPMC5317379 | biostudies-literature
Project description:Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) can typically be categorized into one of four distinct histopathologic patterns of TDP-43 pathology, types A to D. The strength of this histopathologic classification lies in the association between FTLD-TDP subtypes and various clinical and genetic features of disease. Seven cases of FTLD-TDP were identified here which were difficult to classify based on existing pathologic criteria. Distinct features common to these cases included TDP-43 aggregates over a wide neuroanatomic distribution comprised of granulofilamentous neuronal inclusions, abundant grains, and oligodendroglial inclusions. TDP-43 aggregates were phosphorylated and associated with loss of normal nuclear TDP-43 protein (nuclear clearance) but were negative for ubiquitin. Biochemical analysis confirmed the presence of insoluble and phosphorylated TDP-43 and also revealed a distinct pattern of TDP-43 C-terminal fragments relative to other FTLD-TDP subtypes. Finally, these cases were uniformly associated with a very rapid clinical course culminating in death within ~3 years of disease onset. We suggest that these cases may represent a unique clinicopathologic subtype of FTLD-TDP which we provisionally call "type E." The immature appearance of TDP-43 aggregates, widespread distribution, uniform biochemical profile and rapid clinical course highlights the clinical and pathologic variability within FTLD-TDP, and raises the possibility that type E neuropathology is the sequelae of a particularly virulent strain of TDP-43 proteinopathy.
| S-EPMC5521959 | biostudies-literature
Project description:Mutations in the progranulin (PGRN) gene cause a tau pathology-negative and TDP43 pathology-positive form of frontotemporal lobar degeneration (FTLD-TDP). We generated a knock-in mouse harboring the R504X mutation (PGRN-KI). Phosphoproteomic analysis of this model revealed activation of signaling pathways connecting PKC and MAPK to tau prior to TDP43 aggregation and cognitive impairments, and identified PKCα as the kinase responsible for the early-stage tau phosphorylation at Ser203. Disinhibition of Gas6 binding to Tyro3 due to PGRN reduction results in activation of PKCα via PLCγ, inducing tau phosphorylation at Ser203, mislocalization of tau to dendritic spines, and spine loss. Administration of a PKC inhibitor, B-Raf inhibitor, or knockdown of molecules in the Gas6-Tyro3-tau axis rescues spine loss and cognitive impairment of PGRN-KI mice. Collectively, these results suggest that targeting of early-stage and aggregation-independent tau signaling represents a promising therapeutic strategy for this disease.
| S-EPMC5789822 | biostudies-literature