Balance between autophagic pathways preserves retinal homeostasis

Rodríguez-Muela, Natalia; Koga, Hiroshi; García-Ledo, Lucía; Villa, Pedro de la; Rosa, Enrique J. de la; Cuervo, Ana María; Boya, Patricia

doi:10.1111/acel.12072

Cited by 155 publications

(174 citation statements)

References 35 publications

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“…It was recently reported that the age-dependent decrease in macroautophagy in the retina was accompanied by a concomitant increase in CMA to help preserve the retina. 22 We found no evidence for increased CMA in retina when Atg5 was deleted in rods as determined by measuring the levels of Lamp2A and Hsc70. It should be noted that in this previous study involving retinal aging, Atg5 was deleted using a NestinCre that deletes Atg5 in all neural precursors beginning at embryonic day 10.5.…”

Section: Discussioncontrasting

confidence: 57%

“…54 Thus, in the retina, Atg5 deletion would occur in rods, Mueller cells, RPE cells, cones, ganglion cells, bipolar cells, etc. making it difficult to determine whether the degenerative effects on the retina or the increase in CMA observed by these authors 22 were the result rod photoreceptor-specific deletion of Atg5 or the cumulative effects of Atg5 deficiency in the other cell types.…”

Section: Discussionmentioning

confidence: 97%

“…CMA is a more selective pathway for degradation of cytosolic proteins that can compensate for the loss of macroautophagy. 2,[20][21][22] Inherited retinal degenerative diseases such as retinitis pigmentosa or Leber's congenital amaurosis are characterized by premature and progressive death of rod and cone photoreceptor cells. 23 These diseases are characterized by the loss of night vision due to the death of rods followed by the loss of cones leading to diminished visual acuity and a reduction in the quality of life for patients.…”

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confidence: 99%

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confidence: 99%

“…Augmenting autophagy would increase the supply of nutrients to stressed cells and accelerate removal of damaged proteins thereby prolonging cell survival beyond what would be possible by only preventing cell death. Although canonical 22,[30][31][32][33] and noncanonical autophagic mechanisms 34 have been detected in the eye, our knowledge of basic autophagy functions in this organ is still limited. In order to understand how autophagy maintains retinal homeostasis and function, we undertook studies to examine the consequences of deleting the essential autophagy gene Atg5 in rod photoreceptors.…”

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Autophagy supports survival and phototransduction protein levels in rod photoreceptors

et al. 2015

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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...

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Section: Discussioncontrasting

confidence: 57%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Autophagy supports survival and phototransduction protein levels in rod photoreceptors

et al. 2015

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Chaperone‐mediated autophagy: Molecular mechanisms, biological functions, and diseases

Yao,

Shen

2023

MedComm

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Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway that eliminates substrate proteins through heat‐shock cognate protein 70 recognition and lysosome‐associated membrane protein type 2A‐assisted translocation. It is distinct from macroautophagy and microautophagy. In recent years, the regulatory mechanisms of CMA have been gradually enriched, including the newly discovered NRF2 and p38–TFEB signaling, as positive and negative regulatory pathways of CMA, respectively. Normal CMA activity is involved in the regulation of metabolism, aging, immunity, cell cycle, and other physiological processes, while CMA dysfunction may be involved in the occurrence of neurodegenerative disorders, tumors, intestinal disorders, atherosclerosis, and so on, which provides potential targets for the treatment and prediction of related diseases. This article describes the general process of CMA and its role in physiological activities and summarizes the connection between CMA and macroautophagy. In addition, human diseases that concern the dysfunction or protective role of CMA are discussed. Our review deepens the understanding of the mechanisms and physiological functions of CMA and provides a summary of past CMA research and a vision of future directions.

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Role of Chaperone-Mediated Autophagy in Ageing and Neurodegeneration

Ferreira

Pereira

Girão

2015

Current Topics in Neurotoxicity

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Depending on the mechanism and molecular players involved in the targeting of a substrate to the lysosome, autophagy can be divided in three different subtypes: Macroautophagy, Microautophagy and Chaperone-Mediated Autophagy (CMA).In contrast to other forms of autophagy, in CMA, soluble cytosolic proteins can be targeted selectively for degradation in lysosomes. Selectivity in CMA is conferred by the presence of a pentapeptide motif in the amino acid sequence of the substrate proteins, biochemically related to KFERQ, that is recognized by the cytosolic chaperone Hsc70, which results in the targeting of substrates to the lysosome. Once at the lysosomal surface, the substrate-chaperone complex binds to the membrane, and, after unfolding the substrate, is translocated into the lumen by LAMP2A, that acts as the resident a CMA "receptor".CMA has been implicated both in the elimination of parts of the proteome damaged by stressors, as well as, in the selective turnover of substrates directly related with several proteinophaties, most notably in neurodegenerative diseases. In this chapter we will focus on the role of CMA in age-related neurodegeneration and how CMA often becomes the target of the toxic effect of neurodegeneration-related aberrant substrates. The mulfactorial nature of the CMA role in neurodegenerative disorders makes the careful analyses of the evidences gathered thus far instrumental for the understanding of CMA in the context of these diseases.

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Balance between autophagic pathways preserves retinal homeostasis

Cited by 155 publications

References 35 publications

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

Autophagy supports survival and phototransduction protein levels in rod photoreceptors

Chaperone‐mediated autophagy: Molecular mechanisms, biological functions, and diseases

Role of Chaperone-Mediated Autophagy in Ageing and Neurodegeneration

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