Autophagy in neuropathology

Abstract

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above has shown that this 'self-eating' process not only participates in the disposal of intracellular misfolded or "outdated" long-lived proteins, unnecessary/excessive or damaged organelles, but also is a supportive response to provide nutrients and energy to cells exposed to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...