Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3

Chandrasekaran, Abinaya; Dittlau, Katarina Stoklund; Corsi, Giulia I.; Haukedal, Henriette; Doncheva, Nadezhda T.; Ramakrishna, Sarayu; Ambardar, Sheetal; Salcedo, Claudia; Schmidt, Sissel Ida; Zhang, Yu; Cirera, Susanna; Pihl, Maria; Schmid, Benjamin; Nielsen, Troels Tolstrup; Nielsen, Jørgen E.; Kolko, Miriam; Kobolák, Julianna; Dinnyés, András; Hyttel, Poul; Palakodeti, Dasaradhi; Gorodkin, Jan; Muddashetty, Ravi; Meyer, Morten; Aldana, Blanca I.; Freude, Kristine

doi:10.1016/j.stemcr.2021.09.013

Cited by 27 publications

(22 citation statements)

References 64 publications

(74 reference statements)

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“…To evaluate the role of astrocytes in ALS, we differentiated hiPSCs from two ALS-patients with FUS mutations (R521H and P525L) and their corresponding CRISPR-Cas9 gene-edited isogenic controls (R521R and P525P) [ 25 , 27 , 28 ] into astrocytes using a slightly modified version of a recently published protocol [ 29 ]. The P525L mutation causes an aggressive juvenile form of ALS, while the more common R521H mutation causes adult-onset ALS [ 27 ], and the inclusion of both lines demonstrate a broad disease-onset spectrum.…”

Section: Resultsmentioning

confidence: 99%

“…For the former group, a downregulation of HOTAIR (HOX transcript antisense RNA), STAT3 (signal transducer and activator of transcription 3) and Interferon signalling among others suggests a collective attempt to inhibit an immune response. Especially, HOTAIR regulates the NFκB-pathway [ 68 ], which is a major activator of the immune system response [ 69 ] and is involved in several neurodegenerative disorders [ 29 , 70 ] including ALS [ 71 , 72 ]. Notably, PI3K/AKT and BEX2 signalling, which were upregulated in R521H and P525L astrocytes, respectively, are also involved in NFκB-activation [ 73 – 77 ], and this dysregulation supports the heterogeneous reactive response observed in our astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…hiPSC-derived astrocytes were generated using a slightly modified version of a recently published protocol [ 29 ]. In brief, hiPSCs were dissociated with collagenase type IV (Cat N° 10780004), and the cell clusters were collected in Corning® ultra-low attachment flasks (Sigma-Aldrich, St. Louis, MO, USA, Cat N° 734–4140) to support embryoid body (EB) formation.…”

Section: Methodsmentioning

confidence: 99%

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FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

Dittlau

Terrie

Baatsen

et al. 2023

Mol Neurodegeneration

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Background Astrocytes play a crucial, yet not fully elucidated role in the selective motor neuron pathology in amyotrophic lateral sclerosis (ALS). Among other responsibilities, astrocytes provide important neuronal homeostatic support, however this function is highly compromised in ALS. The establishment of fully human coculture systems can be used to further study the underlying mechanisms of the dysfunctional intercellular interplay, and has the potential to provide a platform for revealing novel therapeutic entry points. Methods In this study, we characterised human induced pluripotent stem cell (hiPSC)-derived astrocytes from FUS-ALS patients, and incorporated these cells into a human motor unit microfluidics model to investigate the astrocytic effect on hiPSC-derived motor neuron network and functional neuromuscular junctions (NMJs) using immunocytochemistry and live-cell recordings. FUS-ALS cocultures were systematically compared to their CRISPR-Cas9 gene-edited isogenic control systems. Results We observed a dysregulation of astrocyte homeostasis, which resulted in a FUS-ALS-mediated increase in reactivity and secretion of inflammatory cytokines. Upon coculture with motor neurons and myotubes, we detected a cytotoxic effect on motor neuron-neurite outgrowth, NMJ formation and functionality, which was improved or fully rescued by isogenic control astrocytes. We demonstrate that ALS astrocytes have both a gain-of-toxicity and loss-of-support function involving the WNT/β-catenin pathway, ultimately contributing to the disruption of motor neuron homeostasis, intercellular networks and NMJs. Conclusions Our findings shine light on a complex, yet highly important role of astrocytes in ALS, and provides further insight in to their pathological mechanisms. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

Dittlau

Terrie

Baatsen

et al. 2023

Mol Neurodegeneration

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“…In another study on FTD3, it was shown that a point mutation in the CHMP2B (charged multivesicular body protein 2B), causes aberrant autophagy that in turn triggers perturbed mitochondrial dynamics with impaired glycolysis, increased ROS and elongated mitochondrial morphology, indicating increased mitochondrial fusion in FTD3 astrocytes. This alteration in astrocyte homeostasis prompts a reactive astrocyte phenotype and elevated release of toxic cytokines, which accumulate in NF-κB (nuclear factor kappa b) pathway activation leading to neurodegeneration [16] (Fig. 2).…”

Section: Astrocytic Mitochondria and Their Contribution In Neurodegen...mentioning

confidence: 99%

Cell-Type Specific Mitochondrial Quality Control in the Brain: A Precise Mechanism of Neurodegeneration

Ragupathy¹,

Vukku²,

Barodia³

2023

Preprint

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Neurodegeneration is an age-dependent progressive phenomenon with no defined cause. Aging is the main risk factor for neurodegenerative diseases. During aging, activated microglia undergoes phenotypic alterations that can lead to neuroinflammation, which is well accepted event in the pathogenesis of neurodegenerative diseases. Several common mechanisms are shared by genetically or pathologically distinct neurodegenerative diseases, such as excitotoxicity, mitochondrial deficits and oxidative stress, protein misfolding and translational dysfunction, autophagy and microglia activation. Progressive loss of neuronal population due to increased oxidative stress leads to neurodegenerative diseases mostly due to the accumulation of dysfunctional mitochondria. Mitochondrial dysfunction and excessive neuroinflammatory responses are both sufficient to induce pathology in age-dependent neurodegeneration. Therefore, mitochondrial quality control is key determinant for the health and survival of neuronal cells in the brain. Research has been primarily focused to demonstrate the significance of neuronal mitochondrial health, despite the important contributions of non-neuronal cells that constitutes significant portion of the brain volume. Moreover, mitochondrial morphology and function are distinctly diverse in different tissues; however, little is known about their molecular diversity among cell types. Mitochondrial dynamics and quality in different cell types markedly decides the fate of overall brain health, therefore it is not justifiable to overlook non-neuronal cells and their significant and active contribution in facilitating overall neuronal health. In this review article, we aim to discuss the mitochondrial quality control of different cell types in the brain and how important and remarkable is the diversity and highly synchronized connecting property of non-neuronal cells in keeping the neurons healthy to control neurodegeneration.

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“…ICC, MitoTracker TM , WB, TEM and qPCR were performed according to previously described protocols (56). Image processing and analysis was performed in Fiji ImageJ 2.0.0-rc-65/1.51s.…”

Section: Microscopy and Qpcrmentioning

confidence: 99%

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer’s disease neurons

Haukedal

Corsi

Gadekar

et al. 2022

Preprint

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Alzheimer's disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied Amyloid beta (Ab) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD disease phenotypes, such as increased Ab secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.

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Astrocytic reactivity triggered by defective autophagy and metabolic failure causes neurotoxicity in frontotemporal dementia type 3

Cited by 27 publications

References 64 publications

FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

FUS-ALS hiPSC-derived astrocytes impair human motor units through both gain-of-toxicity and loss-of-support mechanisms

Cell-Type Specific Mitochondrial Quality Control in the Brain: A Precise Mechanism of Neurodegeneration

Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer’s disease neurons

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