Selective Autophagy Receptors in Neuronal Health and Disease

Neurons are electrically excitable, postmitotic cells that perform sensory, relaying, and motor functions. Because of their unique morphological and functional specialization, cells of this type are sensitive to the stress caused by accumulation of misfolded proteins or damaged organelles. Autophagy is the fundamental mechanism that ensures sequestration of cytosolic material and its subsequent degradation in lysosomes of eukaryotic cells, thereby providing cell-autonomous nutrients and removing harmful cargos. Strikingly, mice and flies lacking functional autophagy develop early onset progressive neurodegeneration. Like in human neurodegenerative diseases (NDDs)—Alzheimer's disease, Parkinson's disease, frontotemporal dementia, Huntington's disease, and amyotrophic lateral sclerosis—characteristic protein aggregates observed in autophagy-deficient neurons in the animal models are indicators of the ongoing neuronal pathology. A number of selective autophagy receptors (SARs) have been characterized that interact both with the cargo and components of the autophagic machinery, thus providing the molecular basis for selective degradation of sizable cytosolic components. Interference with autophagy in experimental models, but also during the pathological vagaries in neurons, will thus have far-reaching consequences for a range of selective autophagy pathways critical for the normal functioning of the nervous system. Here, we review the key principles behind the selective autophagy and discuss how the SARs may be involved in the pathogenesis of NDDs. Using recently published examples, we also examine the emerging role of less well studied selective autophagy pathways in neuronal health and disease. We conclude by discussing targeting selective autophagy as an emerging therapeutic modality in NDDs. [Display omitted] •Principles of selective autophagy.•Main selective autophagy receptors (SARs).•Roles of different SARs and selective autophagy pathways in neurodegenerative diseases (NDDs).•Potential therapeutic approaches to NDDs exploiting SARs and selective autophagy.