Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology

Zhang, Shengnan; Lu, Jianping; Liu, Zhenying; Lobato, Amanda G; Zeng, Wen; Liu, Jiaqi; Qiang, Jiali; Zeng, Shuyi; Zhang, Yaoyang; Liu, Cong; Li, Jun; He, Zhuohao; Zhai, R. Grace; Li, Dan

doi:10.7554/elife.79898

Cited by 10 publications

(6 citation statements)

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“…Molecular chaperone is an important element in controlling the protein quality ( Hartl et al, 2011 ). Several proteins have been reported to, respectively, bind and exert chaperone functions in the aggregation of α-synuclein, tau, TDP-43 and FUS amyloids ( Burmann et al, 2020 ; Li et al, 2022 ; Lu et al, 2022 ; Zhang et al, 2022 ). For example, Hsp27 is reported to effectively reduce the aggregation of tau in vitro ( Baughman et al, 2018 ), and rescue tau pathology in transgenic drosophila and mouse models ( Abisambra et al, 2010 ; Zhang et al, 2022 ).…”

Section: Perspective Mechanisms Underlying Co-pathologiesmentioning

confidence: 99%

“…Several proteins have been reported to, respectively, bind and exert chaperone functions in the aggregation of α-synuclein, tau, TDP-43 and FUS amyloids ( Burmann et al, 2020 ; Li et al, 2022 ; Lu et al, 2022 ; Zhang et al, 2022 ). For example, Hsp27 is reported to effectively reduce the aggregation of tau in vitro ( Baughman et al, 2018 ), and rescue tau pathology in transgenic drosophila and mouse models ( Abisambra et al, 2010 ; Zhang et al, 2022 ). It is possible that those molecular chaperones could bind and stabilize different proteins, but the chaperon functions are variable to different proteins, leading to the co-pathogenesis.…”

Section: Perspective Mechanisms Underlying Co-pathologiesmentioning

confidence: 99%

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Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Han¹,

He²

2023

Front. Aging Neurosci.

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Comorbidity is a common phenotype in Parkinson’s disease (PD). Patients with PD not only have motor deficit symptoms, but also have heterogeneous non-motor symptoms, including cognitive impairment and emotional changes, which are the featured symptoms observed in patients with Alzheimer’s disease (AD), frontotemporal dementia (FTD) and cerebrovascular disease. Moreover, autopsy studies have also confirmed the concomitant protein pathogenesis, such as the co-existences of α-synuclein, amyloid-β and tau pathologies in PD and AD patients’ brains. Here, we briefly summarize the recent reports regarding the comorbidity issues in PD from both clinical observations and neuropathological evidences. Furthermore, we provide some discussion about the perspective potential mechanisms underlying such comorbidity phenomenon, with a focus on PD and related neurodegenerative diseases.

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Section: Perspective Mechanisms Underlying Co-pathologiesmentioning

confidence: 99%

Section: Perspective Mechanisms Underlying Co-pathologiesmentioning

confidence: 99%

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Han¹,

He²

2023

Front. Aging Neurosci.

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“… 10 Tau phosphorylation at Ser262 and Ser356 was previously shown to promote phosphorylation at other Alzheimer’s disease-associated phospho-epitopes such as AT100 (phosphorylation at Thr212 and Ser214) and AT8 (phosphorylation at Ser202 and Thr205). 11 Tau phosphorylation at Ser262 and Ser356 affects its interactions with chaperone complexes and degradation, 12 , 13 intracellular distribution, 14 and liquid–liquid phase separation. 15 Substitution of these sites by non-phosphorylatable alanines dramatically reduces tau toxicity in Drosophila models, 11 , 16 , 17 suggesting that phosphorylation at these sites is critical for tau toxicity.…”

Section: Introductionmentioning

confidence: 99%

Mark4 ablation attenuates pathological phenotypes in a mouse model of tauopathy

Sultanakhmetov,

Limlingan,

Fukuchi

et al. 2024

Brain Communications

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Accumulation of abnormally phosphorylated tau proteins is linked to various neurodegenerative diseases, including Alzheimer’s disease and frontotemporal dementia. Microtubule affinity-regulating kinase 4 (MARK4) has been genetically and pathologically associated with Alzheimer’s disease and reported to enhance tau phosphorylation and toxicity in Drosophila and mouse traumatic brain-injury models but not in mammalian tauopathy models. To investigate the role of MARK4 in tau-mediated neuropathology, we crossed P301S tauopathy model (PS19) and Mark4 knockout mice. We performed behavior, biochemical, and histology analyses to evaluate changes in PS19 pathological phenotype with and without Mark4. Here, we demonstrated that Mark4 deletion ameliorated the tau pathology in a mouse model of tauopathy. In particular, we found that PS19 with Mark4 knockout showed improved mortality and memory compared with those bearing an intact Mark4 gene. These phenotypes were accompanied by reduced neurodegeneration and astrogliosis in response to the reduction of pathological forms of tau, such as those phosphorylated at Ser356, AT8-positive tau, and thioflavin S-positive tau. Our data indicate that MARK4 critically contributes to tau-mediated neuropathology, suggesting that MARK4 inhibition may serve as a therapeutic avenue for tauopathies.

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“…Studies have found that NMDA receptor activity‐dependent dynamic microtubule invasion into the spine can promote spine enlargement and induce a long‐lasting enhancement of synaptic transmission (Hoogenraad & Akhmanova, 2010; Hu et al, 2008; Jaworski et al, 2009), which contributes to the pathogenesis of neuropathic pain (Ji et al, 2003; Kuner, 2010; Wilson et al, 2005). Because of their high expression levels in the brain (Drewes et al, 1997), MARK1 and MARK2 were widely studied for their roles in dendrite and spine morphogenesis, and they were found to contribute to the plasticity of microtubules needed for normal functionality of neuronal dendrites and spine phenotypes (Biernat et al, 2002; Wu et al, 2012; Zhang et al, 2022). In addition, MARK2 knockout mice show decreased learning and memory ability and other phenotypes (Segu et al, 2008), and MARK1 is overexpressed in certain brain regions of autistic patients (Maussion et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

A novel role for microtubule affinity‐regulating kinases in neuropathic pain

Shi,

Sun,

Wang

et al. 2024

British J Pharmacology

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Background and PurposeNeuropathic pain affects millions of patients but there are currently few viable therapeutic options available. Microtubule affinity‐regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodeling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain.Experimental ApproachA rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARKs inhibitor. The cognitive function, anxiety‐like behaviors and motor coordination capability were also examined in SNL rats. Synaptic remodeling‐associated signaling changes were detected with electrophysiological recording, Golgi‐Cox staining, western blotting and qRT‐PCR.Key ResultsMARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain‐like behaviors along with improved cognitive deficit, anxiogenic‐like behaviors and motor coordination in SNL rats. Inhibition of MARKs signaling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signaling pathways both in amygdala and spinal dorsal horn.Conclusion and ImplicationsThese results suggest that MARKs‐mediated synaptic remodeling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.

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Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology

Cited by 10 publications

References 59 publications

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Concomitant protein pathogenesis in Parkinson’s disease and perspective mechanisms

Mark4 ablation attenuates pathological phenotypes in a mouse model of tauopathy

A novel role for microtubule affinity‐regulating kinases in neuropathic pain

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