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KCNJ2 inhibition mitigates mechanical injury in human brain organoids

ABSTRACT: Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain itself and which strategies most potently mitigate these processes, particularly in individuals genetically predisposed to neurodegeneration. We developed a high-intensity ultrasound platform to inflict mechanical injury to iPSC-derived cortical organoids. Mechanically injured organoids elicit several classic hallmarks of TBI including neuron death, tau phosphorylation, and TDP-43 phosphorylation and nuclear egress. We found that deep layer excitatory neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes loss-of-function and cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuron death after brain injury, and we present a scalable, genetically-flexible cerebral organoid model that may enable identification of additional modifiers downstream of mechanical stress.

ORGANISM(S): Homo sapiens

PROVIDER: GSE259432 | GEO | 2024/03/04

REPOSITORIES: GEO

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KCNJ2 inhibition mitigates mechanical injury in human brain organoids [scRNA-seq]

Project description:Traumatic brain injury (TBI) strongly correlates with neurodegenerative disease. However, it remains unclear which neurodegenerative mechanisms are intrinsic to the brain itself and which strategies most potently mitigate these processes, particularly in individuals genetically predisposed to neurodegeneration. We developed a high-intensity ultrasound platform to inflict mechanical injury to iPSC-derived cortical organoids. Mechanically injured organoids elicit several classic hallmarks of TBI including neuron death, tau phosphorylation, and TDP-43 phosphorylation and nuclear egress. We found that deep layer excitatory neurons were particularly vulnerable to injury and that TDP-43 proteinopathy promotes loss-of-function and cell death. Injured organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) patients displayed exacerbated TDP-43 dysfunction. Using genome-wide CRISPR interference screening, we identified a mechanosensory channel, KCNJ2, whose inhibition potently mitigated neurodegenerative processes in vitro and in vivo, including in C9ORF72 ALS/FTD organoids. Thus, targeting KCNJ2 may reduce acute neuron death after brain injury, and we present a scalable, genetically-flexible cerebral organoid model that may enable identification of additional modifiers downstream of mechanical stress.

2024-03-04 | GSE260532 | GEO

Premature polyadenylation-mediated loss of stathmin-2 is a hallmark of TDP-43-dependent neurodegeneration

Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with loss of nuclear TDP-43. Here we identify that TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-mRNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from sporadic ALS patients and familial ALS patients with expansion in C9orf72, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity. Thus, premature polyadenylation-mediated reduction in stathmin-2 is a hallmark of ALS/FTD that functionally links reduced nuclear TDP-43 function to enhanced neuronal vulnerability.

2019-01-01 | GSE122069 | GEO

Abnormal RNA stability in amyotrophic lateral sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA binding protein TDP-43. TDP-43 regulatesRNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We used Bru-seq and BruChase-seq to assessgenome-wide RNA stabilityinALS patient-derived cells,demonstratingprofound destabilization of ribosomal and mitochondrial transcripts. This pattern wasrecapitulatedbyTDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in post-mortem samples from ALS and FTD patients. Proteomics and functional studies illustrated corresponding reductionsin mitochondrial components and compensatory increasesin protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, ultimately causing cell death by disrupting energy production and protein synthesis pathways.

2018-07-25 | GSE115310 | GEO

Transcriptomic profiling of purified mature olfactory sensory neurons from transgenic mice expressing genomically encoded double-stranded RNA

Project description:Triggers of innate immune signaling in the CNS of amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) patients remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. Presence of cdsRNA in human brains was coincident with cytoplasmic TDP-43 inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced Type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction, and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in ALS/FTD patients.

2021-03-01 | GSE166307 | GEO

Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Here we show unexpectedly that the signature of hnRNP H sequestration and altered splicing of target transcripts we identified in C9ALS patients (Conlon et al. 2016) also occurs in fully half of 50 post-mortem sporadic, non-C9 ALS/FTD post-mortem brains. Furthermore, and equally surprisingly, these “like-C9” brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum.

2018-07-13 | GSE116622 | GEO

RNA instability in amyotrophic lateral sclerosis

Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) share key features, including accumulation of the RNA binding protein TDP-43. TDP-43 regulates RNA homeostasis, but it remains unclear whether RNA stability is affected in these disorders. We use Bru-seq and BruChase-seq to assess genome-wide RNA stability in ALS patient-derived cells, demonstrating profound destabilization of ribosomal and mitochondrial transcripts. This pattern is recapitulated by TDP-43 overexpression, suggesting a primary role for TDP-43 in RNA destabilization, and in post-mortem samples from ALS and FTD patients. Proteomics and functional studies illustrate corresponding reductions in mitochondrial components and compensatory increases in protein synthesis. Collectively, these observations suggest that TDP-43 deposition leads to targeted RNA instability in ALS and FTD, and may ultimately cause cell death by disrupting energy production and protein synthesis pathways.

2018-07-24 | PXD009969 | Pride

Nanopore sequencing of UNC13A from SHSY5Y and patient RNA

Project description:UNC13A contains a novel cryptic exon which is expressed upon TDP-43 knockdown. However, it also features TDP-43 regulated intron retention of a downstream intron. To investigate the correlation of these two events, we performed Nanopore sequencing of amplicons from SHSY5Y cells with inducible TDP-43 knockdown, and FTD patient RNA samples

2022-02-10 | E-MTAB-11244 | biostudies-arrayexpress

Truncated stathmin-2 is a marker of TDP-43 pathology in frontotemporal dementia

Project description:No treatment for frontotemporal dementia (FTD), the second most common type of early-onset dementia, is available, but therapeutics are being investigated to target the 2 main proteins associated with FTD pathological subtypes: TDP-43 (FTLD-TDP) and tau (FTLD-tau). Testing potential therapies in clinical trials is hampered by our inability to distinguish between patients with FTLD-TDP and FTLD-tau. Therefore, we evaluated truncated stathmin-2 (STMN2) as a proxy of TDP-43 pathology, given the reports that TDP-43 dysfunction causes truncated STMN2 accumulation. Truncated STMN2 accumulated in human induced pluripotent stem cell–derived neurons depleted of TDP-43, but not in those with pathogenic TARDBP mutations in the absence of TDP-43 aggregation or loss of nuclear protein. In RNA-Seq analyses of human brain samples from the NYGC ALS cohort, truncated STMN2 RNA was confined to tissues and disease subtypes marked by TDP-43 inclusions. Last, we validated that truncated STMN2 RNA was elevated in the frontal cortex of a cohort of patients with FTLD-TDP but not in controls or patients with progressive supranuclear palsy, a type of FTLD-tau. Further, in patients with FTLD-TDP, we observed significant associations of truncated STMN2 RNA with phosphorylated TDP-43 levels and an earlier age of disease onset. Overall, our data uncovered truncated STMN2 as a marker for TDP-43 dysfunction in FTD.

2020-10-20 | GSE153960 | GEO

Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms

Project description:Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here, we show that nano-size polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. Additionally, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing TDP-43’s condensation and solidification. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

2024-04-19 | GSE264018 | GEO

TDP-43, an ALS/FTD causal gene, regulates SREBF2-mediated cholesterol metabolism in the CNS

Project description:Maintaining cholesterol homeostasis is essential for health of all animal cells. Because of blood-brain barrier, de novo cholesetrol biosynthesis and intercellular cholesterol transport is thought to maintain cholesterol homeostasis within the central nervous system (CNS). Here, we showed that TDP-43, the pathological signature protein for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), regulates SREBF2-mediated cholesterol metabolism in the central nervous system (CNS). Unbiased transcriptomic analysis of mice with oligodendroglial TDP-43 deletion revealed a progressive and pathway-wide disruption in the cholesterol metabolism correlating with reduced myelination and cholesterol level. Molecularly, TDP-43 binds directly to mRNA of SREBF2, the master transcription regulator for cholesterol metabolism, and multiple mRNAs encoding proteins in the cholesterol biosynthesis and uptake, including HMGCR, HMGCS1, and LDLR. Depletion of TDP-43 leads to reduced SREBF2 and cholesterol level in vitro and in vivo. The cholesterol reduction can be rescued by reintroducing either the nuclear portion of SREBF2 or LDLR, the latter of which is the receptor for cholesterol-containing low-density lipoproteins (LDLs). Furthermore, LDLR are observed to co-aggregate with pathological TDP-43 in oligodendrocytes of FTD patients and motor neurons of sporadic ALS patients. Taken together, our data indicates that TDP-43 is required to maintain SREBF2-dependent cholesterol homeostasis in the CNS, and disturbance of cholesterol metabolism may be involved in ALS, FTD and TDP-43 proteinopathies-related disease.

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