MAPT genotype-dependent mitochondrial aberration and ROS production trigger dysfunction and death in cortical neurons of patients with hereditary FTLD

Korn, Lisanne; Speicher, Anna M.; Schroeter, Christina B.; Gola, Lukas; Kaehne, Thilo; Engler, Alexander; Disse, Paul; Fernández‐Orth, Juncal; Csatári, Júlia; Naumann, Michael; Seebohm, Guiscard; Meuth, Sven G.; Schöler, Hans R.; Wiendl, Heinz; Kovač, Stjepana; Pawlowski, Matthias

doi:10.1016/j.redox.2022.102597

Cited by 9 publications

(7 citation statements)

References 58 publications

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“…Increased membrane potential in mitochondria alongside a spontaneous calcium oscillation leading to mitochondrial hyperphosphorylation and ROS production has been recently reported in cortical neurons carrying the N297K mutation. Furthermore, Korn et al were able to show that specific proteome clusters regulating apoptosis, ROS homeostasis, and mitochondrial function are primarily misregulated by the N297K mutation [ 58 ]. Together with our data, this shows that N297K mutation leads to defective mitochondria in different types of neurons.…”

Section: Discussionmentioning

confidence: 99%

MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons

Hartmann,

Anskat,

Ehrlich

et al. 2024

Biomedicines

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Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons

Hartmann,

Anskat,

Ehrlich

et al. 2024

Biomedicines

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“…Mapt is a protein primarily expressed in neurons of the central nervous system and is involved in various microtubule-related functions, serving as a vital component of the neuronal cytoskeleton (Avila et al, 2004 ). In neurons, Mapt, after post-translational modification, not only regulates the stable transport and distribution of mitochondria (Korn et al, 2023 ), but may also affect the energy production and release of mitochondria through microtubule networks, as well as the apoptosis and survival processes of neurons (Caceres and Kosik, 1990 ; Hartmann et al, 2024 ). Studies have indicated that excessive acetylation of Mapt can impede its depolymerisation process.…”

Section: Discussionmentioning

confidence: 99%

Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation

Zhang,

Wang,

Dou

et al. 2024

Front. Mol. Neurosci.

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AimsWhite matter damage (WMD) is linked to both cerebral palsy and cognitive deficits in infants born prematurely. The focus of this study was to examine how caffeine influences the acetylation of proteins within the neonatal white matter and to evaluate its effectiveness in treating white matter damage caused by hypoxia-ischemia.Main methodsWe employed a method combining affinity enrichment with advanced liquid chromatography and mass spectrometry to profile acetylation in proteins from the white matter of neonatal rats grouped into control (Sham), hypoxic-ischemic (HI), and caffeine-treated (Caffeine) groups.Key findingsOur findings included 1,999 sites of lysine acetylation across 1,123 proteins, with quantifiable changes noted in 1,342 sites within 689 proteins. Analysis of these patterns identified recurring sequences adjacent to the acetylation sites, notably YKacN, FkacN, and G *** GkacS. Investigation into the biological roles of these proteins through Gene Ontology analysis indicated their involvement in a variety of cellular processes, predominantly within mitochondrial locations. Further analysis indicated that the acetylation of tau (Mapt), a protein associated with microtubules, was elevated in the HI condition; however, caffeine treatment appeared to mitigate this over-modification, thus potentially aiding in reducing oxidative stress, inflammation in the nervous system, and improving mitochondrial health. Caffeine inhibited acetylated Mapt through sirtuin 2 (SITR2), promoted Mapt nuclear translocation, and improved mitochondrial dysfunction, which was subsequently weakened by the SIRT2 inhibitor, AK-7.SignificanceCaffeine-induced changes in lysine acetylation may play a key role in improving mitochondrial dysfunction and inhibiting oxidative stress and neuroinflammation.

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“…In addition, two genes, MAPT and HLA (human leukocyte antigen), and 10 pathways such as proteolytic signatures, overlap between AD and PD [ 69 , 70 ]. Studies have shown that the tauopathy-related MAPT variants and the synucleinopathy-associated SNCA mutation may make neurons more vulnerable to cellular dysfunction such as mitochondrial deficits, setting similar mechanistic paths towards neurodegenerative cell death [ 71 ].…”

Section: Genetic Overlap Between Tauopathies and Synucleinopathiesmentioning

confidence: 99%

Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration

Li,

2024

Transl Neurodegener

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Proteinopathy, defined as the abnormal accumulation of proteins that eventually leads to cell death, is one of the most significant pathological features of neurodegenerative diseases. Tauopathies, represented by Alzheimer’s disease (AD), and synucleinopathies, represented by Parkinson’s disease (PD), show similarities in multiple aspects. AD manifests extrapyramidal symptoms while dementia is also a major sign of advanced PD. We and other researchers have sequentially shown the cross-seeding phenomenon of α-synuclein (α-syn) and tau, reinforcing pathologies between synucleinopathies and tauopathies. The highly overlapping clinical and pathological features imply shared pathogenic mechanisms between the two groups of disease. The diagnostic and therapeutic strategies seemingly appropriate for one distinct neurodegenerative disease may also apply to a broader spectrum. Therefore, a clear understanding of the overlaps and divergences between tauopathy and synucleinopathy is critical for unraveling the nature of the complicated associations among neurodegenerative diseases. In this review, we discuss the shared and diverse characteristics of tauopathies and synucleinopathies from aspects of genetic causes, clinical manifestations, pathological progression and potential common therapeutic approaches targeting the pathology, in the aim to provide a timely update for setting the scheme of disease classification and provide novel insights into the therapeutic development for neurodegenerative diseases.

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MAPT genotype-dependent mitochondrial aberration and ROS production trigger dysfunction and death in cortical neurons of patients with hereditary FTLD

Cited by 9 publications

References 58 publications

MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons

MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons

Caffeine improves mitochondrial dysfunction in the white matter of neonatal rats with hypoxia-ischemia through deacetylation: a proteomic analysis of lysine acetylation

Overlaps and divergences between tauopathies and synucleinopathies: a duet of neurodegeneration

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