Abstract
Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles. Autophagy is a process of bulk lysosomal degradation that eliminates these harmful substances and maintains the subcellular environmental quality. In support of autophagy’s importance in neuronal homeostasis, several genetic mutations that interfere with autophagic processes were found to be associated with familial neurodegenerative disorders. In addition, genetic mutations in autophagy-regulating genes provoked neurodegenerative phenotypes in animal models. The Drosophila model significantly contributed to these recent developments, which led to the theory that autophagy dysregulation is one of the major underlying causes of human neurodegenerative disorders. In the current review, we discuss how studies using Drosophila enhanced our understanding of the relationship between autophagy and neurodegenerative processes.
Highlights
Neurodegenerative diseases in humans are frequently associated with prominent accumulation of toxic protein inclusions and defective organelles
ATG1 (ULK1), which complexes with ATG13 and ATG17 (FIP200), is a protein kinase whose activity is critical for the initiation of autophagy [10]
We showed that Atg1/ULK1 and Sestrin, another autophagy regulator [10,42,43], are critical for eliminating damaged mitochondria and maintaining functional and structural integrity of cardiac and skeletal muscle [44]
Summary
Neurodegeneration is a progressive loss of neuronal structure and function, resulting in an irreversible decline in cognitive abilities such as memory and decision-making, as well as bodily coordination and mobility. Of the many different types of neurodegeneration, the most notable and common forms include Alzheimer’s, Parkinson’s and Huntington’s diseases. These diseases manifest with distinct clinical features and affect different regions of the brain, they share very similar molecular pathologies at the cellular level, such as the accumulation of misfolded protein aggregates, which are toxic to the cells [1]. Huntington’s disease exhibits protein inclusions, consisting of a mutant Huntingtin protein that has a polyglutamine expansion. In addition to the protein aggregates, these diseases exhibit an accumulation of dysfunctional mitochondria, which produces excessive reactive oxygen species that damage cellular macromolecules such as DNA, lipids and proteins [2]. The accumulation of protein inclusions and damaged mitochondria are often considered histological hallmarks of neurodegeneration
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