Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies

Abstract

The inherited peripheral neuropathies (IPNs) comprise a growing list of genetically heterogeneous diseases. With mutations in more than 80 genes being reported to cause IPNs, a wide spectrum of functional consequences is expected to follow this genotypic diversity. Hence, the search for a common pathomechanism among the different phenotypes has become the holy grail of functional research into IPNs. During the last decade, studies on several affected genes have shown a direct and/or indirect correlation with autophagy. Autophagy, a cellular homeostatic process, is required for the removal of cell aggregates, long-lived proteins and dead organelles from the cell in double-membraned vesicles destined for the lysosomes. As an evolutionarily highly conserved process, autophagy is essential for the survival and proper functioning of the cell. Recently, neuronal cells have been shown to be particularly vulnerable to disruption of the autophagic pathway. Furthermore, autophagy has been shown to be affected in various common neurodegenerative diseases of both the central and the peripheral nervous system including Alzheimer's, Parkinson's, and Huntington's diseases. In this review we provide an overview of the genes involved in hereditary neuropathies which are linked to autophagy and we propose the disruption of the autophagic flux as an emerging common pathomechanism. We also shed light on the different steps of the autophagy pathway linked to these genes. Finally, we review the concept of autophagy being a therapeutic target in IPNs, and the possibilities and challenges of this pathway-specific targeting.

Keywords: Charcot-Marie-Tooth; autophagy; hereditary neuropathies; neurodegeneration; proteostasis.

FIGURE 1

The different steps of the autophagic pathway. The autophagic pathway consists of several steps. The initiation step is governed by the initiation complex composed of ULK1 and ULK2 (unc-51 like autophagy activating kinase 1/2), RB1CC1 (RB1 inducible coiled-coil 1) and ATG13 and under the control of the nutrient sensing mechanistic target of rapamaycin (MTORC1) complex. After the initiation step, the nucleation of early autophagic membranes is controlled by the nucleation complex consisting of phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3/VPS34), beclin 1 (BECN1), and phosphoinositide-3-kinase regulatory subunit 4 (PIK3R4/VPS15). BECN1 acts as an autophagy check point by interacting with ATG14, UVRAG (UV radiation resistance associated), and apoptosis regulator BCL2 proteins. The formed phagophore then undergoes elongation to become a fully closed double-membraned autophagosome. This step involves 2 conjugation systems resulting in the formation of ATG12-ATG5-ATG16L1 complex via ATG7 and ATG10 action, and of the autophagosomal marker LC3II via the action of ATG4, ATG7, and ATG3. The delivery of membranes to forming autophagosomes is served by ATG9-containing vesicles. The completed autophagosome then fuses with a lysosome becoming an autolysosome where its cargo is subjected to lysosomal degradation. The colors and shapes of the boxes are randomly assigned and show that they are different proteins belonging to the same complexes.

FIGURE 2

Effects of the different IPN-associated genes on the autophagy pathway. Inherited peripheral neuropathy associated genes disrupt autophagy at various levels. Several affected proteins disrupt the initiation of autophagy by inhibiting the initiation complex these include: peripheral myelin protein 22 (PMP22), involved in more than 50% of IPNs, transient receptor potential cation channel subfamily V member 4 (TRPV4), and leucine rich repeat and sterile alpha motif containing 1 (LRSAM1). Others overstimulate the initiation step such as: VAMP associated protein B (VAPB), WNK lysine deficient protein kinase 1 (WNK1), seipin lipid droplet biogenesis associated (Seipin), and DnaJ heat shock protein family (Hsp40) member B2 (DNAJB2). Mutations affecting mitochondrial proteins can inhibit autophagy by causing an abnormal increase in mitophagy and disrupting the autophagy/mitophagy balance: mitofusin 2 (MFN2) and ganglioside induced differentiation associated protein 1 (GDAP1) (left inset). Mutant ER-resident family with sequence similarity 134 member B (FAM134B) affects its role in reticulophagy (right inset). The cyto-protective N-myc downstream regulated 1 (NDRG1) inhibits the initiation complex or stimulates the nucleation complex depending on the physiological triggers. At the nucleation step, mutant tectonin beta-propeller repeat containing 2 (TECPR2) disrupts the formation of early autophagic membranes from the ER. The elongation of the phagophore into an autophagosome is disrupted by mutations that affect the supply for forming membranes from late endosomes: lipopolysaccharide induced TNF factor (LITAF) and SH3 domain and tetratricopeptide repeats 2 (SH3TC2), and from ATG9-containing vesicles as in the microtubules associated proteins: kinesin family member 1A (KIF1A) and Dynamin 2 (DNM2). This step can also be overstimulated by mutations in the tyrosine kinase A (TrkA) which lead to toxic increase in ATG12-ATG5 conjugates. The transport of autophagosomes to lysosomes is disrupted by mutations affecting cytoskeleton associated proteins such as Dynactin 1 (DCTN1) and dystonin (DST). Mutations involving Ras-related GTPase (RAB7), valosin containing protein (VCP), heat shock protein B8 (HSPB8), and the phosphatases: phosphoinositide 5-phosphatase (FIG4), and myotubularin-related proteins (MTMR2 and MTMR13) block the lysosomal fusion step in autophagy. Mutant chaperonin containing TCP1 subunit 5 (CCT5) on the other hand inhibits the degradation step. In addition, several mutant proteins lead to the formation of aggregates which basal autophagy on its own might not cope with (PMP22, Seipin, LITAF, HSPB8) and neurofilament light (NEFL). The colors and shapes of the boxes are randomly assigned and show that they are different proteins belonging to the same complexes.