Autophagy and Human Genetic Disease

ABSTRACT

• Autophagy is an intracellular bulk degradation system.

• The genetics, signalling and regulation of autophagy have been a major focus of research for the last decade and consequently these are increasingly well understood.

• Defects in autophagy are now known to underpin a number of Mendelian human genetic diseases including multiple sulfatase deficiency, mucopolysaccharidosis type IIIA, X-linked myopathy with excessive autophagy, Danon disease, Pompe disease, and some forms of familial frontotemporal lobar degeneration. Autophagy may also be involved in familial forms of Parkinson’s disease. Furthermore, genome wide association studies are identifying autophagy as an important process underlying risk alleles for more complex polygenic diseases, such as Crohn’s disease.

• Autophagy can be induced or inhibited by a number of physiological and pharmacological stimuli.

• Manipulation of autophagy with drugs is a promising therapeutic strategy for a number of human genetic diseases characterised by aggregation of abnormal proteins. These diseases include polyglutamine diseases, such as Huntington’s disease and some familial forms of frontotemporal lobar degeneration and Parkinson’s disease. This is important, as there are currently no treatments which modify the rate of neurodegeneration in these conditions.

INTRODUCTION

The first descriptions of what we now call macroautophagy were made nearly half a century ago by the Nobel Laureate Christian de Duve, when he described membrane-bound vesicles in the cytoplasm, their subsequent fusion with lysosomes, and degradation of their contents¹. Macroautophagy is the most studied and best characterised form of autophagy. Of the two other sorts of autophagy which have subsequently been described, microautophagy occurs when small portions of cytoplasm are directly engulfed by the lysosomal membrane², while chaperone mediated autophagy involves the uptake of proteins marked with a specific pentapeptide motif into lysosomes via lysosomal-associated membrane protein 2 (LAMP-2a). Though interest has increased in these latter two forms of autophagy, particularly in chaperone mediated autophagy and its potential links to Parkinson’s disease³, they remain relatively poorly understood, compared to macroautophagy. Indeed, following de Duve’s initial description, even macroautophagy remained a relatively neglected cellular phenomena for the best part of the next 40 years. However, in the last ten years, a number of events have led to an exponential increase in the amount of research in this area, reflected in a similar rise in publications on the topic¹. The rest of this chapter will concentrate on macroautophagy, which we will subsequently refer to simply as ‘autophagy’.

One of the key breakthroughs underpinning recent progress was the identification of autophagy in yeast in the early 1990s and the subsequent identification of the key genes involved in the process in this organism. Later identification of the mammalian homologues of many of these so-called ATG genes⁴, and in particular of Atg8/LC3 in the year 2000, has allowed the development of more accurate ways of measuring autophagic activity^5,6. However, the real spur for increased interest in autophagy has come ...