Protéinopathie | EPFL Graph Search

En médecine, les protéinopathies font référence à une classe de maladies dans lesquelles certaines protéines deviennent structurellement anormales et perturbent ainsi la fonction des cellules, des tissus et des organes du corps. Souvent, les protéines ne parviennent pas à se replier dans leur configuration normale ; dans cet état mal replié, les protéines peuvent devenir toxiques (en acquérant de nouvelles fonctions indésirées par mutation) ou perdre leur fonction normale. Les protéinopathies (également connues sous le nom de troubles de conformation des protéines ou des maladies de repliement protéique) comprennent des maladies telles que la maladie de Creutzfeldt-Jakob et autres maladies à prions, la maladie d'Alzheimer, de Parkinson , les amyloses, l'atrophie multisystématisée, et un large éventail d'autres troubles. Le terme anglais proteopathy a été proposé pour la première fois en 2000 par Lary Walker et Harry LeVine. Le concept de protéinopathie trouver

Role of the FoxO3a Transcription Factor in alpha-synuclein Induced Neurodegeneration

Emilda Pino

Increased expression of α-synuclein and point mutations in its amino acid sequence play a causative role in familial forms of Parkinson's disease (PD). In addition, circumstances affecting the level of α-synuclein expression significantly increase the risk of developing sporadic PD. This is further corroborated by the abundance of α-synuclein in protein aggregates called Lewy bodies (LBs), a histological hallmark of the disease. Aging constitutes the most prominent risk factor in the pathogenesis of PD and other synucleinopathies. Protective stress response and repair pathways gradually decline over time, a process likely to contribute to the appearance of neurodegenerative disease. Studies in lower organisms, such as the yeast and the worm Caenorhabditis elegans, have highlighted the role of the evolutionarily conserved transcription factor FoxO3a in the aging process, increasing life span and reducing molecular processes that possibly underlie neurodegeneration in higher organisms. This transcription factor is mainly controlled by insulin/Insulin-like growth factor (IGF) signaling (IIS) and impacts a broad range of disease-related responses involving neuronal apoptosis and adaptation to stress. We have hypothesized that FoxO3a activity may regulate the response of dopaminergic neurons to PD-related stress such as reactive oxygen species (ROS) and α-synuclein proteotoxicity. To address this question, AAV2/6 vectors encoding various forms of FoxO3a were used to modulate the activity of this transcription factor in the adult rat substantia nigra pars compacta (SNpc). We determined a viral dose where expression of the wild-type form of FoxO3a did not impair the survival of nigral neurons and their striatal projections. In contrast, a constitutively active FoxO3a mutant (FoxOm), with an Akt-independent nuclear import, led to a significant loss of dopaminergic cell bodies, consistent with the pro-apoptotic activity of FoxO3a. Expression of a dominant-negative competitor composed of the FoxO DNA-binding domain (FoxODBD) did not significantly impair the survival of nigral neurons. However, at a high viral dose, FoxO inhibition led to neuronal accumulation of 4-hydroxynonenal (HNE), an indicator of chronic oxidative stress, and to a loss of neurons positive for dopaminergic markers. Altogether, these results confirm in nigral neurons the critical role of FoxO3a activity at the intersection between apoptotic response and neuronal resistance to oxidative stress. Next, we hypothesized that FoxO3a may regulate the response of dopaminergic neurons to α-synuclein proteotoxicity. To investigate the effect of FoxO3a on α-synuclein accumulation, we co-injected AAV2/6 vectors modulating FoxO3a activity with a wild-type human α-synuclein vector. When compared to control and FoxOm, both wild-type FoxO3a and FoxODBD significantly reduced the α-synuclein-induced loss of neurons positive for dopaminergic markers. Importantly, the injection of vectors activating FoxO3a (wild-type and FoxOm) led to an overall reduction in soluble α-synuclein monomeric forms, concomitant with the formation of dense proteinase K-resistant aggregates found in the neuronal cell soma. With the dominant negative FoxODBD, we observed an accumulation of α-synuclein, with a diffuse distribution of proteinase K-resistant immunoreactivity in both axon and neuronal soma. These data point to FoxO3a as an important regulator of neuronal survival in the SNpc, which can oppose α-synuclein accumulation and proteotoxicity. The role of FoxO3a in α-synuclein toxicity may provide some clues about the role of the aging process in PD neurodegeneration.

EPFL2012

Enhancing mitochondrial quality control to fight neuromuscular degeneration in aging and disease

Mario Romani

Loss of mitochondrial function and proteostasis typify aging and age-associated degenerative disorders such as Alzheimer's disease and muscle aging. To date, no cure or preventive measure is available to manage these conditions. Alterations of cellular proteostasis, such as accumulation of misfolded or aggregated proteins, can directly affect mitochondrial homeostasis leading to activation of specific mitochondrial stress pathways capable of maintaining mitochondrial function. However, the contribution of these pathways in age-associated diseases characterized by proteotoxic aggregates is largely unknown. My thesis aims to understand the connection between cellular and mitochondrial proteostasis with a particular focus on mitochondrial stress pathways involved in the response to proteotoxic stress. To this end, I performed 2 studies: Reduction of Amyloid-beta proteotoxicity through activation of mitochondrial quality control: Accumulation of Amyloid-beta (Aß) peptidic aggregates, generated by the miscleavage of amyloid precursor protein (APP), is often associated with mitochondrial dysfunction. However, it is largely unknown how mitochondria react to these proteotoxic insults. We identified a cross-species conserved mitochondrial stress response, from nematodes to humans, activated during Aß proteotoxic stress. This response entails key mitochondrial quality control pathways such as the mitochondrial unfolded protein response (UPRmt) and mitophagy. Importantly, activation of these pathways through administration of mitochondrial regulators Doxycycline and the NAD+ booster nicotinamide riboside (NR), was sufficient to reduce Aß accumulation and proteotoxicity in nematodes and human cell lines. Moreover, boosting mitochondrial quality control in vivo in a mouse model of Alzheimer's disease with the compound NR led to a reduction of brain Aß plaques and preservation of cognitive function. Skeletal muscle aging is characterized by amyloid-like protein aggregates: Skeletal muscle aging is characterized by accumulation of dysfunctional mitochondria and misfolded proteins. However, the connection between these two hallmarks of muscle aging remains elusive. We found that aged skeletal muscles present a similar perturbation of mitochondrial and APP processing pathways when compared to muscles from inclusion body myositis patients (IBM), a disease characterized by intracellular protein deposits containing also Aß aggregates. In line with this, we identified amyloid-like aggregates in aged muscle closely resembling the ones observed during IBM with concomitant mitochondrial dysfunction. Strategies aiming at restoring mitochondrial homeostasis led to activation of the mitochondrial quality control accompanied by a reduction of amyloid-like aggregates in vitro and in vivo in mammalian and nematode systems. In summary, our work demonstrated that amyloidosis characterizes muscle, and possibly brain, aging in a similar fashion to what is observed in muscle and brain tissues from IBM and Alzheimer's patients, respectively. Importantly, restoring mitochondrial homeostasis through activation of mitochondrial quality control is sufficient to alleviate protein aggregation and improve tissue function in aging, IBM and Alzheimer's disease models.

EPFL2021

Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity

Johan Auwerx, Norman Lionel Moullan, Francesca Potenza, Solene Rietsch, Adrian Schmid, Vincenzo Sorrentino, Hongbo Zhang

Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-beta peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-beta proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-beta proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-beta proteotoxic diseases, such as Alzheimer's disease.