Alterations of autophagy in the peripheral neuropathy Charcot-Marie-Tooth type 2B

Abstract

Charcot-Marie-Tooth type 2B (CMT2B) disease is a dominant axonal peripheral neuropathy caused by 5 mutations in the RAB7A gene, a ubiquitously expressed GTPase controlling late endocytic trafficking. In neurons, RAB7A also controls neuronal-specific processes such as NTF (neurotrophin) trafficking and signaling, neurite outgrowth and neuronal migration. Given the involvement of macroautophagy/autophagy in several neurodegenerative diseases and considering that RAB7A is fundamental for autophagosome maturation, we investigated whether CMT2B-causing mutants affect the ability of this gene to regulate autophagy. In HeLa cells, we observed a reduced localization of all CMT2B-causing RAB7A mutants on autophagic compartments. Furthermore, compared to expression of RAB7AWT, expression of these mutants caused a reduced autophagic flux, similar to what happens in cells expressing the dominant negative RAB7AT22N mutant. Consistently, both basal and starvation-induced autophagy were strongly inhibited in skin fibroblasts from a CMT2B patient carrying the RAB7AV162M mutation, suggesting that alteration of the autophagic flux could be responsible for neurodegeneration.

MAPK15 is part of the ULK complex and controls its activity to regulate early phases of the autophagic process

“…Based on ATG12-ATG5 localization on isolation membranes, puncta formed by these endogenous protein conjugates, detected by immunofluorescence, can be used to monitor the specific formation of early autophagosomal membranes (27). We therefore monitored the formation of ATG12 puncta in full medium and upon serum starvation, a stimulus for early autophagosomal biogenesis (28), and as shown above, we demonstrated that these vesicles strongly increased upon MAPK15 overexpression in both conditions (Fig. 8).…”

“…Next, we also sought to collect functional data supporting the interaction of MAPK15 with the biogenesis of autophagosomes. Specifically, we evaluated the effects of MAPK15 overexpression on the protein levels of endogenous ATG12-ATG5 complexes, which represent a measure of the formation of early-stage autophagosomes, as already demonstrated in our laboratory (28). With this approach, we demonstrated that levels of the ATG12-ATG5 complex increased, in full medium and starvation conditions, upon MAPK15 overexpression, whereas two mutants, MAPK15 KD and MAPK15 AXXA (specifically affecting the ability of this kinase of inducing autophagy without disturbing its kinase activity) (16), prevented starvation-dependent induction of early autophagosomal biogenesis ( Fig.…”

Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization

“…The liver microenvironment is naturally more conducive to cells that display a high glycolytic profile and are adapted for a low-oxygen state. This is illustrated by the abundance of studies demonstrating that primary hepatocellular carcinomas preferentially engage in glycolytic metabolism to proliferate in the liver (Jiao et al, 2017; Lin et al, 2017; Song et al, 2015). It is therefore tempting to speculate that to colonize the liver, metastasizing cancer cells from other organs must be able to overcome this hypoxic barrier in order to adapt to the hepatic environment.…”

Impaired proteostasis in rare neurological diseases

“…mutant genes have been linked with over a dozen distinct RNDs in which either formation and/or maturation of autophagosomes is impaired [9,18,69,70,119,121,[126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141]. For instance, lysosomal-associated membrane glycoprotein 2 (LAMP2), which is involved in autophagosome maturation, cause Danon disease, a rare genetic condition characterized by muscle weakening and intellectual disability [127].…”