Figure 3 - uploaded by Maria Manczak
Content may be subject to copyright.
Co-IP analysis of phosphorylated tau and Drp1 in AD patients. ( A ) IP results with a phosphorylated tau antibody and results from western blot analysis with the Drp1 antibody. Drp1 was found in phosphorylated tau-IP elutes in the cortical tissues from AD patients. ( B ) Western blots of protein lysates from AD patients and control subjects, using the phosphorylated tau antibody.
Source publication
We recently reported increased mitochondrial fission and decreased fusion, increased amyloid beta (Aβ) interaction with the mitochondrial fission protein Drp1, increased mitochondrial fragmentation, impaired axonal transport of mitochondria and synaptic degeneration in neurons affected by AD. In the present study, we extended our previous investiga...
Contexts in source publication
Context 1
... verify our co-IP results and our western blot results, we performed IP with phosphorylated tau and western blot with the Drp1 antibody. As shown in Figure 3A, phosphorylated tau-IP elutes from AD patients (lanes 2 and 3) revealed a 82 kDa Drp1 protein, further confirming the interaction between Drp1 and phosphorylated tau in AD patients. Our western blot analysis of lysates from AD patients (lanes 5 and 6) and control subjects (lane 4) using the Drp1-specific antibody found a 82 kDa band, indicating that the 82 kDa band is specific for Drp1 (Fig. 3B). ...
Context 2
... (lanes 2 and 3) revealed a 82 kDa Drp1 protein, further confirming the interaction between Drp1 and phosphorylated tau in AD patients. Our western blot analysis of lysates from AD patients (lanes 5 and 6) and control subjects (lane 4) using the Drp1-specific antibody found a 82 kDa band, indicating that the 82 kDa band is specific for Drp1 (Fig. ...
Similar publications
Extensive changes in neural tissue structure and function accompanying Alzheimer’s disease (AD) suggest that intrinsic signal
optical imaging can provide new contrast mechanisms and insight for assessing AD appearance and progression. In this work,
we report the development of a wide-field spatial frequency domain imaging (SFDI) method for non-cont...
Citations
... For instance, S-glutathionylation regulates mitofusins (Mfn1/Mfn2), crucial players in the mitochondrial fusion process [182]. Dynamin-related protein 1 (Drp1), a protein involved in mitochondrial fission, is activated by S-nitrosylation [183], and high levels of S-nitrosylated Drp1 have been reported in postmortem brains of AD patients [184]. In addition, a recent study has shown that H2S promoted mitophagy by increasing S-sulfhydration of ubiquitin-specific peptidase 8 (USP8), which in turn enhanced Parkin deubiquitination and recruitment to damaged mitochondria (Figure 4) [185]. ...
Oxidation–reduction post-translational modifications (redox-PTMs) are chemical alterations to amino acids of proteins. Redox-PTMs participate in the regulation of protein conformation, localization and function, acting as signalling effectors that impact many essential biochemical processes in the cells. Crucially, the dysregulation of redox-PTMs of proteins has been implicated in the pathophysiology of numerous human diseases, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. This review aims to highlight the current gaps in knowledge in the field of redox-PTMs biology and to explore new methodological advances in proteomics and computational modelling that will pave the way for a better understanding of the role and therapeutic potential of redox-PTMs of proteins in neurodegenerative diseases. Here, we summarize the main types of redox-PTMs of proteins while providing examples of their occurrence in neurodegenerative diseases and an overview of the state-of-the-art methods used for their detection. We explore the potential of novel computational modelling approaches as essential tools to obtain insights into the precise role of redox-PTMs in regulating protein structure and function. We also discuss the complex crosstalk between various PTMs that occur in living cells. Finally, we argue that redox-PTMs of proteins could be used in the future as diagnosis and prognosis biomarkers for neurodegenerative diseases.
... Second, mitochondria dysfunction might arise from factors other than oxidative stress / oxidative damage and thus would be unchanged by DMSO or R-carvedilol treatment. One possible alternative dysfunction is an early increase in the level of mitochondrial fission protein, DRP1, as reported in patients and APP/PS1 mice [116][117][118]. It has been suggested that mitochondria are reflective sources, and thus increased mitochondrial fragmentation could increase MCP/AR as measured by OCT [119,120]. ...
Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also occur in Nnt-intact 5xFAD mice and whether these biomarkers can be pharmacologically treated. Four-month-old wild-type or 5xFAD C57BL/6 substrains with either a null (B6J) Nnt or intact Nnt gene (B6NTac) and 5xFAD B6J mice treated for one month with either R-carvedilol + vehicle or only vehicle (0.01% DMSO) were studied. The contrast sensitivity (CS), external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness (a proxy for low pH-triggered water removal), profile shape of the hyperreflective band just posterior to the ELM (i.e., the mitochondrial configuration within photoreceptors per aspect ratio [MCP/AR]), and retinal laminar thickness were measured. Both wild-type substrains showed similar visual performance indices and dark-evoked ELM-RPE contraction. The lack of a light–dark change in B6NTac MCP/AR, unlike in B6J mice, is consistent with relatively greater mitochondrial efficiency. 5xFAD B6J mice, but not 5xFAD B6NTac mice, showed lower-than-WT CS. Light-adapted 5xFAD substrains both showed abnormal ELM-RPE contraction and greater-than-WT MCP/AR contraction. The inner retina and superior outer retina were thinner. Treating 5xFAD B6J mice with R-carvedilol + DMSO or DMSO alone corrected CS and ELM-RPE contraction but not supernormal MCP/AR contraction or laminar thinning. These results provide biomarker evidence for prodromal photoreceptor mitochondrial dysfunction/oxidative stress/oxidative damage, which is unrelated to visual performance, as well as the presence of the Nnt gene. This pathophysiology is druggable in 5xFAD mice.
... In AD has been observed the presence of Aβ in the mitochondria. This presence of Aβ generates hyperphosphorylated tau proteins by interacting with mitochondrial Drp1 protein, which, in turn, disrupts microtubule function and induces neural toxicity [184,185]. Moreover, mitochondrial Aβ can also interact with Aβ-binding alcohol dehydrogenase (ABAD), leading to mitochondrial dysfunction and the production of ROS [186]. ...
Intercellular mitochondrial transfer (MT) is a newly discovered form of cell-to-cell signalling involving the active incorporation of healthy mitochondria into stressed/injured recipient cells, contributing to the restoration of bioenergetic profile and cell viability, reduction of inflammatory processes and normalisation of calcium dynamics. Recent evidence has shown that MT can occur through multiple cellular structures and mechanisms: tunneling nanotubes (TNTs), via gap junctions (GJs), mediated by extracellular vesicles (EVs) and other mechanisms (cell fusion, mitochondrial extrusion and migrasome-mediated mitocytosis) and in different contexts, such as under physiological (tissue homeostasis and stemness maintenance) and pathological conditions (hypoxia, inflammation and cancer). As Mesenchimal Stromal/ Stem Cells (MSC)-mediated MT has emerged as a critical regulatory and restorative mechanism for cell and tissue regeneration and damage repair in recent years, its potential in stem cell therapy has received increasing attention. In particular, the potential therapeutic role of MSCs has been reported in several articles, suggesting that MSCs can enhance tissue repair after injury via MT and membrane vesicle release. For these reasons, in this review, we will discuss the different mechanisms of MSCs-mediated MT and therapeutic effects on different diseases such as neuronal, ischaemic, vascular and pulmonary diseases. Therefore, understanding the molecular and cellular mechanisms of MT and demonstrating its efficacy could be an important milestone that lays the foundation for future clinical trials.
... Altogether, our findings reveal a novel role for RNA methylation in regulating mitochondrial function in neuronal cells. Defects in mitochondrial function contribute to neurodegeneration [27][28][29][30][31][32][33], and increasing evidence is implicating dysregulation of RNA methylation in the pathogenesis of neurological disorders [5,[34][35][36][37][38][39]. Therefore, our findings not only provide insights into fundamental mechanisms regulating mitochondrial function mediated by RNA methylation, but also open up new avenues for understanding the pathogenesis of neurological diseases. ...
... Altogether, our findings reveal a novel role for RNA methylation in regulating mitochondrial function in neuronal cells. Defects in mitochondrial function contribute to neurodegeneration [27][28][29][30][31][32][33], and increasing evidence is implicating dysregulation of RNA methylation in the pathogenesis of neurological disorders [5,[34][35][36][37][38][39]. Therefore, our findings not only provide insights into fundamental mechanisms regulating mitochondrial function mediated by RNA methylation, but also open up new avenues for understanding the pathogenesis of neurological diseases. ...
RNA methylation of N6-methyladenosine (m6A) is emerging as a fundamental regulator of every aspect of RNA biology. RNA methylation directly impacts protein production to achieve quick modulation of dynamic biological processes. However, whether RNA methylation regulates mitochondrial function is not known, especially in neuronal cells which require a high energy supply and quick reactive responses. Here we show that m6A RNA methylation regulates mitochondrial function through promoting nuclear-encoded mitochondrial complex subunit RNA translation. Conditional genetic knockout of m6A RNA methyltransferase Mettl14 (Methyltransferase like 14) by Nestin-Cre together with metabolomic analysis reveals that Mettl14 knockout-induced m6A depletion significantly downregulates metabolites related to energy metabolism. Furthermore, transcriptome-wide RNA methylation profiling of wild type and Mettl14 knockout mouse brains by m6A-Seq shows enrichment of methylation on mitochondria-related RNA. Importantly, loss of m6A leads to a significant reduction in mitochondrial respiratory capacity and membrane potential. These functional defects are paralleled by the reduced expression of mitochondrial electron transport chain complexes, as well as decreased mitochondrial super-complex assembly and activity. Mechanistically, m6A depletion decreases the translational efficiency of methylated RNA encoding mitochondrial complex subunits through reducing their association with polysomes, while not affecting RNA stability. Together, these findings reveal a novel role for RNA methylation in regulating mitochondrial function. Given that mitochondrial dysfunction and RNA methylation have been increasingly implicate in neurodegenerative disorders, our findings not only provide insights into fundamental mechanisms regulating mitochondrial function, but also open up new avenues for understanding the pathogenesis of neurological diseases.
... Tau accumulation correlates with the production of reactive oxygen species and can phosphorylate Cell Biochemistry and Biophysics and interact with Drp1 to prevent mitochondrial damage [238]. Tau accumulation is associated with reactive oxygen species production and can be phosphorylated and interact with Drp1 to mediate the development of Alzheimer's disease [238][239][240][241][242]. Elevated levels of Drp1 have been found in 3xTg Alzheimer's Mice [243]. ...
Drp1 (Dynamin-Related Protein 1) is a cytoplasmic GTPase protein encoded by the DNM1L gene that influences mitochondrial dynamics by mediating mitochondrial fission processes. Drp1 has been demonstrated to play an important role in a variety of life activities such as cell survival, proliferation, migration, and death. Drp1 has been shown to play different physiological roles under different physiological conditions, such as normal and inflammation. Recently studies have revealed that Drp1 plays a critical role in the occurrence, development, and aggravation of a series of diseases, thereby it serves as a potential therapeutic target for them. In this paper, we review the structure and biological properties of Drp1, summarize the biological processes that occur in the inflammatory response to Drp1, discuss its role in various cancers triggered by the mitochondrial pathway and investigate effective methods for targeting Drp1 in cancer treatment. We also synthesized the phenomena of Drp1 involving in the triggering of other diseases. The results discussed herein contribute to our deeper understanding of mitochondrial kinetic pathway-induced diseases and their therapeutic applications. It is critical for advancing the understanding of the mechanisms of Drp1-induced mitochondrial diseases and preventive therapies.
... Despite this limitation, multiple protein changes were report here as similarly altered in epilepsy and AD have been previously reported as similarly altered in human tissue or genetically linked to epilepsy, thus independently validating our results. Some examples include: Synaptophysin (SYP) is decreased in both epilepsy [39] and AD [32]; SLC17A7 (also known as VGLUT1) is decreased in select TLE cases [16] and AD [23]; DNM1L interacts with tau and accumulates in tau aggregates in AD [31] and is genetically linked to epilepsy [9]; SYN1 is decreased in AD [2] and genetically linked to seizures [29]. ...
The prevalence of epilepsy is increased among Alzheimer’s Disease (AD) patients and cognitive impairment is common among people with epilepsy. Epilepsy and AD are linked but the shared pathophysiological changes remain poorly defined. We aim to identify protein differences associated with epilepsy and AD using published proteomics datasets. We observed a highly significant overlap in protein differences in epilepsy and AD: 89% (689/777) of proteins altered in the hippocampus of epilepsy patients were significantly altered in advanced AD. Of the proteins altered in both epilepsy and AD, 340 were altered in the same direction, while 216 proteins were altered in the opposite direction. Synapse and mitochondrial proteins were markedly decreased in epilepsy and AD, suggesting common disease mechanisms. In contrast, ribosome proteins were increased in epilepsy but decreased in AD. Notably, many of the proteins altered in epilepsy interact with tau or are regulated by tau expression. This suggests that tau likely mediates common protein changes in epilepsy and AD. Immunohistochemistry for Aβ and multiple phosphorylated tau species (pTau396/404, pTau217, pTau231) showed a trend for increased intraneuronal pTau217 and pTau231 but no phosphorylated tau aggregates or amyloid plaques in epilepsy hippocampal sections. Our results provide insights into common mechanisms in epilepsy and AD and highlights the potential role of tau in mediating common pathological protein changes in epilepsy and AD.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00401-024-02683-4.
... Mitochondrial fragmentation is detrimental to cellular bioenergetics. As discussed earlier, the mitochondrial fission protein Drp1 is abnormally expressed in AD, leading to excess mitochondrial fragmentation [194]. Drp1 also interacts with Aβ and hyperphosphorylated tau and promotes changes in mitochondrial morphology and bioenergetics, negatively impacting ATP production. ...
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.
... The researchers also added synaptoneurosomes that were isolated from ALS brain samples to SH-SY5Y cells and discovered that treatment with ALS synaptoneurosomes (SNs), enriched in pTau-S396, increased oxidative stress, induced mitochondrial fragmentation, and altered mitochondrial connectivity in vitro. Because pTau-S396 had previously been shown to interact with GTPase DRP1 40 and ALS SNs were shown to induce mitochondrial fragmentation in vitro, the team hypothesized that increases in pTau-S396 might trigger pathological mitochondrial fission in ALS by binding DRP1. They were able to demonstrate that pTau-S396 did indeed interact with DRP1 and that DRP1 accumulated in SNs across ALS subtypes, leading to increases in mitochondrial fragmentation in ALS. ...
INTRODUCTION
The pace of innovation has accelerated in virtually every area of tau research in just the past few years.
METHODS
In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co‐organized and co‐sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.
RESULTS
Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.
DISCUSSION
The virtual meeting provided an opportunity to foster cross‐sector collaboration and partnerships as well as a forum for updating colleagues on research‐advancing tools and programs that are steadily moving the field forward.
... Compelling evidence demonstrates that excessive activation of extra-synaptic NMDARs by oligomeric Aβ leads to increased p-tau levels, indicating Aβ induced tau hyperphosphorylation. Hyperphosphorylated tau interacts abnormally with the mitochondrial cleavage protein Drp1 in brain autopsies from AD patients, revealing that tau may actively involve in Aβ-induced mitochondrial dysfunction. However, further research is required to discover the exact mechanism [43,44]. Additionally, Jadhav et al. indicated that presynaptic tau protein is associated with synaptic loss and synaptic failure and that low levels of presynaptic protein may be relevant with a growing number of NFTs [45]. ...
Alzheimers Disease (AD) is one of the prime cuases of dementia, responsible for 60% to 70% of cases worldwide, according to the World Health Organization (WHO). Unfortunately, numerous research challenges still remain for this disease, which poses a great threat to human health worldwide, especially in the elderly population. Scientists are still struggling to find the pathogenesis and pathogenic mechanisms of AD, and while research for new tests and novel drugs is ongoing, it faces a high failure rate. This article will summarize some remarkable results to date and discuss future research directions.
