Autophagy gone awry in neurodegenerative diseases

Wong, Esther; Cuervo, Ana María

doi:10.1038/nn.2575

Cited by 825 publications

(705 citation statements)

References 101 publications

(140 reference statements)

Supporting

Mentioning

688

Contrasting

Unclassified

Order By: Relevance

“…Consistently, p62 and Ub immunolabeling on cortical neurons from adult WT and KO brain cortex showed accumulation of labeling positive inclusions (Figure 4c–e). In neurons, misfolded or aggregated proteins are cleared by a coordinated chaperone‐mediated autophagy, macroautophagy, or Ub‐proteasome system (Wong & Cuervo, 2010). Ub‐positive inclusions were noted in autophagy‐impaired Atg5 ‐deficient neurons leading to degeneration and motor dysfunction (Hara et al., 2006).…”

Section: Resultsmentioning

confidence: 99%

FOXO protects against age‐progressive axonal degeneration

Hwang

Santo

et al. 2017

Aging Cell

View full text Add to dashboard Cite

SummaryNeurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age‐progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system‐specific deletion of Foxo transcription factors in mice accelerates aging‐related axonal tract degeneration, which is followed by motor dysfunction. This accelerated neurodegeneration is accompanied by levels of white matter astrogliosis and microgliosis in middle‐aged Foxo knockout mice that are typically only observed in very old wild‐type mice and other aged mammals, including humans. Mechanistically, axonal degeneration in nerve‐specific Foxo knockout mice is associated with elevated mTORC1 activity and accompanying proteotoxic stress due to decreased Sestrin3 expression. Inhibition of mTORC1 by rapamycin treatment mimics FOXO action and prevented axonal degeneration in Foxo knockout mice with accelerated nervous system aging. Defining this central role for FOXO in neuroprotection during mammalian aging offers an invaluable window into the aging process itself.

show abstract

Section: Resultsmentioning

confidence: 99%

FOXO protects against age‐progressive axonal degeneration

Hwang

Santo

et al. 2017

Aging Cell

View full text Add to dashboard Cite

show abstract

“…Recently, an increasing body of evidence suggests that impaired macroautophagy (named autophagy), which is responsible for recycling of damaged organelles and misfolded proteins in conditions of cellular stress, may contribute to the chronic complications of diabetes (Sridhar, Botbol, Macian, & Cuervo, 2012;Varga et al, 2015;Wong & Cuervo, 2010). Thus, experimental data suggests that autophagic turnover may help to maintain healthy mitochondria and energyderived metabolic processes, limiting cellular death pathways, oxidative stress, and protein aggregation in diabetic neuropathy (Yerra, Gundu, Bachewal, & Kumar, 2016).…”

Section: Introductionmentioning

confidence: 99%

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

et al. 2017

View full text Add to dashboard Cite

Objectives: The progression and pathophysiology of neuropathy in impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) is poorly understood, especially in relation to autophagy. This study was designed to assess whether the presence of autophagyrelated structures was associated with sural nerve fiber pathology, and to investigate if endoneurial capillary pathology could predict the development of T2DM and neuropathy. Patients and Methods:Sural nerve physiology and ultrastructural morphology were studied at baseline and 11 years later in subjects with normal glucose tolerance (NGT), IGT, and T2DM.Results: Subjects with T2DM had significantly lower sural nerve amplitude compared to subjects with NGT and IGT at baseline. Myelinated and unmyelinated fiber, endoneurial capillary morphology, and the presence and distribution of autophagy structures were comparable between groups at baseline, except for a smaller myelinated axon diameter in subjects with T2DM and IGT compared to NGT. The baseline values of the subjects with NGT and IGT who converted to T2DM 11 years later demonstrated healthy smaller endoneurial capillary and higher g-ratio versus subjects who remained NGT. At follow-up, T2DM showed a reduction in nerve conduction, amplitude, myelinated fiber density, unmyelinated axon diameter, and autophagy structures in myelinated axons. Endothelial cell area and total diffusion barrier was increased versus baseline. Conclusions:We conclude that small healthy endoneurial capillary may presage the development of T2DM and neuropathy. Autophagy occurs in human sural nerves and can be affected by T2DM. Further studies are warranted to understand the role of autophagy in diabetic neuropathy. K E Y W O R D Sautophagy, diabetes, endoneurial capillary, impaired glucose tolerance, morphometry, peripheral neuropathy

show abstract

“…6 Induced autophagy maintains the amino acid pool inside cells to adapt to starvation while constitutive autophagy has been shown to function as a cell-repair mechanism that is important for long-lived postmitotic cells. [7][8][9][10][11] Defects in autophagy have been associated with neurodegenerative diseases, [12][13][14][15] diabetes, 16,17 lysosomal storage disease 18 and the loss of vision. 19 In addition to macroautophagy, microautophagy and chaperone-mediated autophagy (CMA) have been described.…”

mentioning

confidence: 99%

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

et al. 2015

View full text Add to dashboard Cite

Damage and loss of the postmitotic photoreceptors is a leading cause of blindness in many diseases of the eye. Although the mechanisms of photoreceptor death have been extensively studied, few studies have addressed mechanisms that help sustain these non-replicating neurons for the life of an organism. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomal pathway for degradation. It is not only a major pathway activated in response to cellular stress, but is also important for cytoplasmic turnover and to supply the structural and energy needs of cells. We examined the importance of autophagy in photoreceptors by deleting the essential autophagy gene Atg5 specifically in rods. Loss of autophagy led to progressive degeneration of rod photoreceptors beginning at 8 weeks of age such that by 44 weeks few rods remained. Cone photoreceptor numbers were only slightly diminished following rod degeneration but their function was significantly decreased. Rod cell death was apoptotic but was not dependent on daily light exposure or accelerated by intense light. Although the light-regulated translocation of the phototransduction proteins arrestin and transducin were unaffected in rods lacking autophagy, Atg5-deficient rods accumulated transducin-α as they degenerated suggesting autophagy might regulate the level of this protein.This was confirmed when the light-induced decrease in transducin was abolished in Atg5-deficient rods and the inhibition of autophagy in retinal explants cultures prevented its degradation. These results demonstrate that basal autophagy is essential to the long-term health of rod photoreceptors and a critical process for maintaining optimal levels of the phototransduction protein transducin-α. As the lack of autophagy is associated with retinal degeneration and altered phototransduction protein degradation in the absence of harmful gene products, this process may be a viable therapeutic target where rod cell loss is the primary pathologic event. Autophagy is an intracellular pathway where cytoplasmic constituents are delivered to the lysosomes for degradation. Defective autophagy can contribute to the age-dependent accumulation of damaged proteins and organelles leading to altered cellular homeostasis and loss of function. [1][2][3][4][5] The metabolic roles of autophagy can be classified into two types, basal and induced. In nutrient-rich conditions, autophagy is suppressed but still occurs at low levels (basal autophagy); however, when cells are subjected to stress (starvation, injury, hypoxia), autophagy is activated immediately (induced autophagy). 6 Induced autophagy maintains the amino acid pool inside cells to adapt to starvation while constitutive autophagy has been shown to function as a cell-repair mechanism that is important for long-lived postmitotic cells. 7-11 Defects in autophagy have been associated with neurodegenerative diseases, 12-15 diabetes, 16,17 lysosomal storage disease 18 and the loss of vision. 19 In addition to macroautophagy, m...

show abstract

Autophagy gone awry in neurodegenerative diseases

Cited by 825 publications

References 101 publications

FOXO protects against age‐progressive axonal degeneration

FOXO protects against age‐progressive axonal degeneration

Longitudinal study of neuropathy, microangiopathy, and autophagy in sural nerve: Implications for diabetic neuropathy

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

Contact Info

Product

Resources

About