Autophagy in Rare (NonLysosomal) Neurodegenerative Diseases

Abstract

Neurodegenerative diseases (NDDs) comprise conditions with impaired neuronal function and loss and may be associated with a build-up of aggregated proteins with altered physicochemical properties (misfolded proteins). There are many disorders, and causes include gene mutations, infections, or exposure to toxins. The autophagy pathway is involved in the removal of unwanted proteins and organelles through lysosomes. While lysosomal storage disorders have been described for many years, it is now recognised that perturbations of the autophagy pathway itself can also lead to neurodegenerative disease. These include monogenic disorders of key proteins involved in the autophagy pathway, and disorders within pathways that critically control autophagy through monitoring of the supply of nutrients (mTORC1 pathway) or of energy supply in cells (AMPK pathway). This review focuses on childhood-onset neurodegenerative disorders with perturbed autophagy, due to defects in the autophagy pathway, or in upstream signalling via mTORC1 and AMPK. The review first provides a short description of autophagy, as related to neurons. It then examines the extended role of autophagy in neuronal function, plasticity, and memory. There follows a description of each step of the autophagy pathway in greater detail, illustrated with examples of diseases grouped by the stage of their perturbation of the pathway. Each disease is accompanied by a short clinical description, to illustrate the diversity but also the overlap of symptoms caused by perturbation of key proteins necessary for the proper functioning of autophagy. Finally, there is a consideration of current challenges that need addressing for future therapeutic advances.

Keywords: autophagy; child; neurodegeneration.

Graphical abstract

Fig. 1

Autophagy pathway overview, with childhood-onset neurodegenerative diseases affecting the pathway either directly or indirectly highlighted in red font. Signals that activate the autophagic process (initiation) in response to stress are mediated via mTOR and AMPK pathways and colocalise at the UNC51-like kinase (ULK)1 complex. This complex consists of ULK1, autophagy-related protein 13 (ATG13), RB1-inducible coiled-coil protein 1 (FIP200), and ATG101. This complex then initiates phagophore nucleation by the phosphorylation of proteins in the PI3KC3/VPS34 complex (class III PI3 kinase PI3KC3 also known as vacuolar protein sorting 34 (VPS34), Beclin 1, ATG14, activating molecule in Beclin 1-regulated autophagy protein 1 (AMBRA1) and general vesicular transport factor (p115)). The next step is the activation of phosphatidylinositol-3-phosphate (PI3P) generation at an endoplasmic reticulum structure (Omegasome). PI3P interacts with the effector proteins WD repeat domain phosphoinositide-interacting protein (WIPI1 and 2) and zinc-finger FYVE domain-containing protein 1 (DFCP1), recruiting them to the omegasome via interaction with their PI3P-binding domains. WIPI2 interacts with the ATG12-ATG5-ATG16L1 complex. This complex facilitates ATG3-mediated conjugation of ATG8 proteins, such as microtubule-associated protein light chain 3 (LC3) proteins and gamma-aminobutyric acid receptor-associated proteins (GABARAPS) to membrane-resident phosphatidylethanoloamine (PE). This leads to the formation of lipidated forms that can bind to membranes. ATG8s attract additional proteins in the autophagy pathway containing LC3-interacting regions (LIR). They are required for membrane extension and sealing of the phagophore membrane to create the autophagosome. ATG9-containing vesicles mediate the delivery of some of these membranes. The sealing of the membrane produces the autophagosome. The next step is the removal of the ATG proteins, followed by fusion with lysosomes. Lysosomes contain acid hydrolases, which break down the autophagic cargo, allowing rescued nutrients to be returned to the cytoplasm. TSC, tuberous sclerosis complex; MPAN, mitochondrial membrane protein-associated neurodegeneration; HSP, hereditary spastic paraplegia; NBIA, neurodegeneration with brain iron accumulation. Inhibitory phosphorylation events shown as ‘P’ encircled, in yellow/light gray, activating phosphorylation events shown in red/dark gray.