β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog–Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models

Goiran, Thomas; Duplan, Eric; Chami, Mounia; Bourgeois, Alexandre; Manaa, Wejdane El; Rouland, Lila; Dunys, Julie; Lauritzen, Inger; You, Han; Stambolic, Vuk; Biféri, Maria Grazia; Barkats, Martine; Pimplikar, Sanjay W.; Sergeant, Nicolas; Colin, Morvane; Morais, Vanessa A.; Pardossi‐Piquard, Raphaëlle; Checler, Frédéric; Costa, Cristine Alves da

doi:10.1016/j.biopsych.2017.04.011

Cited by 50 publications

(44 citation statements)

References 75 publications

(88 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was also shown that Aβ molecules can form pores permeable for Ca 2+ in the cell membrane and additionally disturb calcium homeostasis, contributing to the formation of free oxygen radicals. Oxidative stress caused by the accumulation of Aβ and calcium excess may contribute to the mitochondrial dysfunction [44]. Early accumulation of structurally abnormal mitochondria was observed in AD patients and a similar change was observed in AD animal models [43,44].…”

Section: Alzheimer's Diseasementioning

confidence: 90%

The role of mitophagy in selected neurodegenerative diseases

Osuch¹,

Kucharska²,

Chmielewska³

et al. 2019

ppn

View full text Add to dashboard Cite

Purpose: Mitophagy is a type of selective autophagy, associated with degradation of inefficient mitochondria. The modulation of mitophagy seems to be one of the most important solutions for key factors in the maintenance of neuronal cell homeostasis. This paper overviews the role of mitochondria and mitophagy in the etiology of the most common age-related neurodegenerative diseases, i.e. Alzheimer's disease (AD) and Parkinson's disease (PD). Views: In recent years, the role of mitophagy in neurodegenerative diseases has been given more attention. It has been shown that disturbed mitophagy and mitochondrial dysfunction in neurons may contribute to the cell death. In AD and PD, a number of abnormalities related to the expression and function of proteins involved in the process have been revealed. Because mitochondrial dysfunction plays a role in the origin/etiology of those diseases, possible therapeutic strategies aiming to improve quality control systems of mitochondria are also presented. Nowadays, these are mainly strategies improving the energy efficiency and facilitating induction of mitophagy. Conclusions: Recent reports suggest that abnormal function of proteins involved in mitophagy may be an important etiological factor in neurodegenerative diseases. Furthermore, these findings may become the basis for the development of more effective thera pies preventing or alleviating the disease symptoms.

show abstract

Section: Alzheimer's Diseasementioning

confidence: 90%

The role of mitophagy in selected neurodegenerative diseases

Osuch¹,

Kucharska²,

Chmielewska³

et al. 2019

ppn

View full text Add to dashboard Cite

show abstract

“…Mutations in PINK1 and PARK2 contribute to obvious mitochondrial dysfunctions, leading to degeneration of muscles and neurons [ 120 ]. Abnormal mitochondrial accumulation in AD is thought to be caused by multiple mechanisms of mitophagy defects, such as the impaired PS1/γ-secretase–amyloid precursor protein intracellular domain–PINK1 transcription axis [ 121 ]. In PD, PARK6 (coding PINK1) and PARK2 (coding Parkin) gene mutations will cause 5% of familial PD [ 122 ].…”

Section: Main Textmentioning

confidence: 99%

Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases

Huang

Yan

Zhang

2020

Transl Neurodegener

View full text Add to dashboard Cite

Mitochondria are the energy center of cell operations and are involved in physiological functions and maintenance of metabolic balance and homeostasis in the body. Alterations of mitochondrial function are associated with a variety of degenerative and acute diseases. As mitochondria age in cells, they gradually become inefficient and potentially toxic. Acute injury can trigger the permeability of mitochondrial membranes, which can lead to apoptosis or necrosis. Transactive response DNA-binding protein 43 kDa (TDP-43) is a protein widely present in cells. It can bind to RNA, regulate a variety of RNA processes, and play a role in the formation of multi-protein/RNA complexes. Thus, the normal physiological functions of TDP-43 are particularly important for cell survival. Normal TDP-43 is located in various subcellular structures including mitochondria, mitochondrial-associated membrane, RNA particles and stress granules to regulate the endoplasmic reticulum–mitochondrial binding, mitochondrial protein translation, and mRNA transport and translation. Importantly, TDP-43 is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis, frontotemporal dementia and Alzheimer's disease, which are characterized by abnormal phosphorylation, ubiquitination, lysis or nuclear depletion of TDP-43 in neurons and glial cells. Although the pathogenesis of TDP-43 proteinopathy remains unknown, the presence of pathological TDP-43 inside or outside of mitochondria and the functional involvement of TDP-43 in the regulation of mitochondrial morphology, transport, and function suggest that mitochondria are associated with TDP-43-related diseases. Autophagy is a basic physiological process that maintains the homeostasis of cells, including targeted clearance of abnormally aggregated proteins and damaged organelles in the cytoplasm; therefore, it is considered protective against neurodegenerative diseases. However, the combination of abnormal TDP-43 aggregation, mitochondrial dysfunction, and insufficient autophagy can lead to a variety of aging-related pathologies. In this review, we describe the current knowledge on the associations of mitochondria with TDP-43 and the role of autophagy in the clearance of abnormally aggregated TDP-43 and dysfunctional mitochondria. Finally, we discuss a novel approach for neurodegenerative treatment based on the knowledge.

show abstract

“…In the amyloidogenic pathway, C99 is engaged by the heterotetrameric γ‐secretase complex, which binds C99 monomers and initially cuts C99 at either of two possible “epsilon cleavage” sites in the membrane near the cytosol, resulting the in the release of the amyloid intracellular domain (AICD). The function of AICD is controversial, with some evidence suggesting that it plays a role in regulating transcription of certain genes . Intriguingly, some of the these genes encode proteins clearly related to the amyloidogenic pathway or to tau hyperphosphorylation and fibrillization .…”

Section: Components Of the Amyloidogenic Pathwaymentioning

confidence: 99%

The vexing complexity of the amyloidogenic pathway

2019

View full text Add to dashboard Cite

The role of the amyloidogenic pathway in the etiology of Alzheimer's disease (AD), particularly the common sporadic late onset forms of the disease, is controversial. To some degree, this is a consequence of the failure of drug and therapeutic antibody trials based either on targeting the proteases in this pathway or its amyloid end products. Here, we explore the formidable complexity of the biochemistry and cell biology associated with this pathway. For example, we review evidence that the immediate precursor of amyloid-β, the C99 domain of the amyloid precursor protein (APP), may itself be toxic. We also review important new results that appear to finally establish a direct genetic link between mutations in APP and the sporadic forms of AD. Based on the complexity of amyloidogenesis, it seems possible that a major contributor to the failure of related drug trials is that we have an incomplete understanding of this pathway and how it is linked to Alzheimer's pathogenesis. If so, this highlights a need for further characterization of this pathway, not its abandonment.

show abstract

β-Amyloid Precursor Protein Intracellular Domain Controls Mitochondrial Function by Modulating Phosphatase and Tensin Homolog–Induced Kinase 1 Transcription in Cells and in Alzheimer Mice Models

Cited by 50 publications

References 75 publications

The role of mitophagy in selected neurodegenerative diseases

The role of mitophagy in selected neurodegenerative diseases

Maintaining the balance of TDP-43, mitochondria, and autophagy: a promising therapeutic strategy for neurodegenerative diseases

The vexing complexity of the amyloidogenic pathway

Contact Info

Product

Resources

About