An update on autophagy disorders

Abstract

Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, and macromolecular complexes. As autophagy is particularly relevant for cellular homeostasis in post-mitotic tissues, congenital disorders of autophagy, due to monogenic defects in key autophagy genes, share a common "clinical signature" including neurodevelopmental, neurodegenerative, and neuromuscular features, as well as variable abnormalities of the eyes, skin, heart, bones, immune cells, and other organ systems, depending on the expression pattern and the specific function of the defective proteins. Since the clinical and genetic resolution of EPG5-related Vici syndrome, the paradigmatic congenital disorder of autophagy, the widespread use of massively parallel sequencing has resulted in the identification of a growing number of autophagy-associated disease genes, encoding members of the core autophagy machinery as well as related proteins. Recently identified monogenic disorders linking selective autophagy, vesicular trafficking, and other pathways have further expanded the molecular and phenotypical spectrum of congenital disorders of autophagy as a clinical disease spectrum. Moreover, significant advances in basic research have enhanced the understanding of the underlying pathophysiology as a basis for therapy development. Here, we review (i) autophagy in the context of other intracellular trafficking pathways; (ii) the main congenital disorders of autophagy and their typical clinico-pathological signatures; and (iii) the recommended primary health surveillance in monogenic disorders of autophagy based on available evidence. We further discuss recently identified molecular mechanisms that inform the current understanding of autophagy in health and disease, as well as perspectives on future therapeutic approaches.

Keywords: autophagy; cellular trafficking; congenital disorders; neurodegeneration; neurodevelopment.

FIGURE 1

Schematic overview of core autophagy and vesicular trafficking with the genes implicated in the originally described congenital disorders of autophagy highlighted. Upper left: Overview of autophagy from initiation and elongation of a double‐sided membrane to WDR45‐mediated maturation and closure of the autophagosome. Eventually autophagosomes fuse with lysosomes aided by tethering factors such as EPG5 and WDR45, prior to the degradation of defective cargo for recycling through lysosomal acidic hydrolases. Lower right: Overview of endocytosis via vesicles that mature from early to late endosomes/multivesicular bodies mediated by SPG11 and ZFYVE26. Trafficking events between the Golgi apparatus and the endoplasmic reticulum are essential for budding vesicles via mediation by SNX14 for lipid droplets and TECPR2 for autophagosomes. Secretory vesicles may fuse with the plasma membrane for exocytosis. Created with Biorender.com, with permission.

FIGURE 2

An overview of clinical and radiographic features in selected congenital disorders of autophagy. (A‐D) EPG5‐related disorders: Photographs of patients with EPG5‐related Vici syndrome with (A) marked hypopigmentation and subtle neurological findings at an early age and (B) coarse facial features suggestive of a storage disorder in a more severely affected patient. (C) Thalamic changes characterized by low signal on T2‐weighted MRI sequences (asterisks) and (D) high signal on T1‐weighted MRI images (D) (asterisks), modified from. (E–H) WDR45‐related disorders: Facial photographs of patients with WDR45‐related disorders, modified from. (G) T2‐hyperintense globus pallidum iron deposition, and (H) diffuse myelin reduction (white arrow) and prominent lateral ventricles (double arrow), modified from. (I‐L) AP4S1‐related disorders: (I,J) Facial photographs of two patients with AP4S1‐related spastic paraplegia, modified from. (K) T2‐hyperintense signal in the forceps minor consistent with the ears of the lynx sign, and (L) short and round T2‐hyperintense signal in the forceps minor, modified from.