mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy

Perluigi, Marzia; Domenico, Fabio Di; Butterfield, D. Allan

doi:10.1016/j.nbd.2015.03.014

Cited by 259 publications

(191 citation statements)

References 137 publications

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“…In addition, several studies have identified changes with age in signaling pathways (i.e. mTOR, SIRT, FOXO) that could contribute to reduced induction of autophagy and autophagosome formation (Bitto et al., 2014; Park et al., 2016; Perluigi, Di Domenico & Butterfield, 2015; Schiavi & Ventura, 2014). Future analysis will be required to explore the molecular requirements that determine the recruitment of motor proteins to AVs and LYS and the potential impact in this process of age‐associated changes in these signaling routes.…”

Section: Discussionmentioning

confidence: 99%

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

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SummaryInability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.

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Section: Discussionmentioning

confidence: 99%

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

et al. 2018

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“…Based on the absence of neurohistopathologies, such as Lewy bodies and neurofibrillary tangles, in brains of neurodegenerative mice models, the degree of protein aggregation‐related pathology in aging mice may be much milder than that in humans. Activities of the protein degradation systems, such as autophagy and the ubiquitin proteasome system, are compromised in aging62, 63, which suggests that clearance of protein aggregation in aging might be more efficient in mice than in humans. From this perspective, it is probable that toxic gain of function of APN through interaction with tau may be specific to human aging, whereas loss of neuroprotective and neurotrophic functions of APN due to a decreased activity of the insulin/APN receptors signaling network might be common between humans and mice.…”

Section: Differential Action Of Apn In Rodents and Humansmentioning

confidence: 99%

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

Waragai

Ho²,

Takamatsu

et al. 2017

Ann Clin Transl Neurol

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A recent study suggested that insulin resistance may play a central role in the pathogenesis of Alzheimer's disease (AD). In this regard, it is of note that upregulation of plasma adiponectin (APN), a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation, has recently been associated with the severities of amyloid deposits and cognitive deficits in the elderly, suggesting that APN may enhance the risk of AD. These results are unanticipated because AD has been linked to type II diabetes and other metabolic disorders in which hypoadiponectinemia has been firmly established, and because APN ameliorated neuropathological features in a mouse model of neurodegeneration. Therefore, the objective of this study is to discuss the possible mechanisms underlying the biological actions of APN in the context of AD. Given that insulin receptor signaling is required for normal function of the nervous system, we predict that APN may be upregulated to compensate for compromised activity of the insulin receptor signaling pathway. However, increased APN might be sequestered by tau in the brain, leading to neurotoxic protein aggregation in AD. Alternatively, misfolding of APN may result in downregulation of the insulin/APN signal transduction network, leading to decreased neuroprotective and neurotrophic activities. Thus, it is possible that both ‘gain of function’ and ‘loss of function’ of APN may underlie synaptic dysfunction and neuronal cell death in AD. Such a unique biological mechanism underlying APN function in AD may require a novel therapeutic strategy that is distinct from previous treatment for metabolic disorders.

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“…Several studies reveal that DS and Alzheimer's disease (AD) neuropathology have many common features that include deposition of senile plaques and neurofibrillary tangles, together with cellular dysfunction such as mitochondrial defects, increased oxidative stress, and impairment of protein quality control (PQC) (4,27,51,53,57). Around two-thirds of individuals with DS develop dementia in their 50s, but the severity of neuropathology and dementia varies significantly among DS population.…”

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confidence: 99%

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

Tramutola

Domenico

Barone

et al. 2017

Antioxidants & Redox Signaling

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Aims: Among the putative mechanisms proposed to be common factors in Down syndrome (DS) and Alzheimer's disease (AD) neuropathology, deficits in protein quality control (PQC) have emerged as a unifying mechanism of neurodegeneration. Considering that disturbance of protein degradation systems is present in DS and that oxidized/misfolded proteins require polyubiquitinylation for degradation via the ubiquitin proteasome system, this study investigated if dysregulation of protein polyubiquitinylation is associated with AD neurodegeneration in DS. Results: Postmortem brains from DS cases before and after development of AD neuropathology and age-matched controls were analyzed. By selectively isolating polyubiquitinated proteins, we were able to identify specific proteins with an altered pattern of polyubiquitinylation as a function of age. Interestingly, we found that oxidation is coupled with polyubiquitinylation for most proteins mainly involved in PQC and energy metabolism. Innovation: This is the first study showing alteration of the polyubiquitinylation profile as a function of aging in DS brain compared with healthy controls. Understanding the onset of the altered ubiquitome profile in DS brain may contribute to identification of key molecular regulators of age-associated cognitive decline. Conclusions: Disturbance of the polyubiquitinylation machinery may be a key feature of aging and neurodegeneration. In DS, age-associated deficits of the proteolytic system may further exacerbate the accumulation of oxidized/misfolded/polyubiquitinated proteins, which is not efficiently degraded and may become harmful to neurons and contribute to AD neuropathology. Antioxid. Redox Signal. 26,[280][281][282][283][284][285][286][287][288][289][290][291][292][293][294][295][296][297][298]

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mTOR signaling in aging and neurodegeneration: At the crossroad between metabolism dysfunction and impairment of autophagy

Cited by 259 publications

References 137 publications

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

Polyubiquitinylation Profile in Down Syndrome Brain Before and After the Development of Alzheimer Neuropathology

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