Autophagy in neuronal cells: general principles and physiological and pathological functions

Damme, Markus; Suntio, Taina; Säftig, Paul; Eskelinen, Eeva‐Liisa

doi:10.1007/s00401-014-1361-4

Cited by 81 publications

(73 citation statements)

References 263 publications

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“…Knockout of Vps15, or of the kinase Pik3c3 [33], results in muscle pathology very similar to that seen in XMEA, including the presence of AVSF. Of most relevance, overexpression of Vps15 + PIK3C3 in myoblast cell lines from patients with Danon disease resulted in a decrease in aberrant autophagy (as determined by LC3 levels, see [5]) and a reduction in the accumulation of glycogen. Given that there appears to be significant overlap in the pathogenesis of Danon disease and XMEA, a similar upregulation of Vps15/PIK3C3 might improve disease pathology in XMEA as well.…”

Section: Treatment Considerationsmentioning

confidence: 99%

“…It fuses with the lysosome to form the autophagolysosome, where hydrolases activated in the acidic environment contributed by the lysosome degrade the encased cellular components, which can then be reused/ recycled as sources of cellular energy or building blocks for intracellular structures. A general detailed review of autophagy is presented in this issue [5].…”

Section: Introductionmentioning

confidence: 99%

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X-linked myopathy with excessive autophagy: a failure of self-eating

et al. 2015

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Autophagic vacuolar myopathies (AVMs) are a group of disorders united by shared histopathological features on muscle biopsy that include the aberrant accumulation of autophagic vacuoles. The classic conditions that compose the AVMs include Pompe Disease, Danon Disease and X-linked myopathy with excessive autophagy (XMEA). Other disorders, including acquired myopathies like chloroquine toxicity, also have features of an autophagic myopathy. This review is focused on XMEA, a myopathy with onset of slowly progressive proximal weakness and elevated serum creatine kinase (2× to 20× normal) typically in the first decade of life. However, both late-adult onset and severe, sometimes lethal, neonatal cases also occur. Skeletal muscle pathology is characterized by numerous cytoplasmic autophagic vacuoles, complex muscle fiber splitting with internalization of capillaries, and complement C5b-9 deposition within vacuoles and along the sarcolemma. The autophagic vacuoles have sarcolemmal features. Mutations in the VMA21 gene at Xq28 cause XMEA by reducing the activity of lysosomal hydrolases. The VMA21 protein regulates the assembly of the V-ATPase required to acidify the lysosome. Increased lysosomal pH and poor degradation of cellular debris may secondarily induce autophagy, the net effect being accumulation of autophagolysosomes. The relationship of XMEA to other lysosomal disorders of muscle and potential therapeutic interventions for XMEA are discussed.

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Section: Treatment Considerationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

X-linked myopathy with excessive autophagy: a failure of self-eating

et al. 2015

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“…32–34 Perturbation of the autophagic flux indeed causes neurodevelopmental and neurodegenerative diseases and has been observed, for instance, in Alzheimer disease, Parkinson disease and amyotrophic lateral sclerosis. 33 , 34 Notably, RAB7 regulates autophagosomal maturation controlling the final step of maturation of late autophagic vesicles into autolysosomes, presumably involving fusion with lysosomes. 12 , 35–37 …”

Section: Introductionmentioning

confidence: 99%

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

et al. 2018

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Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.

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“…A most important meeting in the lysosomeautophagy research was the Ciba Foundation Symposium on Lysosomes in 1963 [4,10], where de Duve presented a paper "The lysosome concept" and Novikoff presented his characterization of cytolysomes, acid phosphatase-positive organelles-thus, clearly related to lysosomes-which contained various cytoplasmic components, such as mitochondria, ER membranes and ribosomes in an obvious state of disintegration. It was at that important meeting, where therefore they cannot dilute the deleterious burden of toxic substances and dysfunctional organelles by cell division [7]. This vulnerability of nervous tissue is manifest in neurodegenerative diseases, in which accumulation of aggregates of many different types of misfolded or excessive proteins occurs in increasing amounts with ageing (e.g.…”

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confidence: 99%

“…This vulnerability of nervous tissue is manifest in neurodegenerative diseases, in which accumulation of aggregates of many different types of misfolded or excessive proteins occurs in increasing amounts with ageing (e.g. [7,16]). …”

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confidence: 99%

Autophagy in neuropathology

Minassian

Kalimo

2015

Acta Neuropathol

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de Duve suggested the terms endocytosis and exocytosis as well as distinguished heterophagic from autophagic functions of lysosomes, and he succeeded in persuading Novikoff to replace the name cytolysomes with the term autophagic vacuoles. Early simple hypotheses were that lysosomes are "suicide bags" the rupture of which release lytic enzymes leading to physiological autolysis [10] and autophagy serves as a cellular rubbish-disposal mechanism [22]. The highly productive research after the discoveries above has shown that this 'self-eating' process not only participates in the disposal of intracellular misfolded or "outdated" long-lived proteins, unnecessary/excessive or damaged organelles, but also is a supportive response to provide nutrients and energy to cells exposed to various stresses, such as starvation. The history of the rapidly accelerating progress in autophagy research has been reported for example by Yang and Klionsky [22] and Ohsumi [17], all leading figures in this field. From the 1960s to early 1980s, autophagy studies relied on enzyme bio-and histochemistry as well as light and electron microscopic morphology. The "tsunami" of molecular biology and genetics swept over autophagy in the 1990s, when the molecular basis of autophagy began to emerge. This progress has set tough methodological demands to autophagy researchers, as described in the united guideline article by an extensive (well over 1,000 authors) squad of renowned and influential autophagy researchers for the use and interpretation of assays for monitoring autophagy [11].The importance of autophagy in cellular homeostasis is reflected in the vast number of recently published scientific articles, a great share of them dealing with autophagy in neuropathology, i.e. its role in the health and disease of the nervous and muscle tissues. The importance of autophagy in the homeostasis and survival of these two tissues reflects the fact that neurons and mature myofibers are postmitotic cells and Christian de Duve discovered lysosomes [8] by "Exploring Cells with a Centrifuge" as was the title of his Nobel lecture when he in 1974 received the Nobel prize in Physiology and Medicine. He and his team found that acid phosphatase activity in liver homogenates was latent because it was enwrapped in "membrane sacs", membrane-bound organelles, whereby substrates were made inaccessible to this and other hydrolytic enzymes with various specificities and optimal activities at acidic pH. The biochemical discovery was translated into morphology above all by the pioneering electron microscopic studies by Novikoff et al. [14] and Clark [5]. According to de Duve [10] it was Novikoff and Essner [15] and Ashford and Porter [1] who discovered autophagy having made the key morphological observations. A most important meeting in the lysosomeautophagy research was the Ciba Foundation Symposium on Lysosomes in 1963 [4,10], where de Duve presented a paper "The lysosome concept" and Novikoff presented his characterization of cytolysomes, acid phosphatase-positive o...

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Autophagy in neuronal cells: general principles and physiological and pathological functions

Cited by 81 publications

References 263 publications

X-linked myopathy with excessive autophagy: a failure of self-eating

X-linked myopathy with excessive autophagy: a failure of self-eating

Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

Autophagy in neuropathology

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