Chaperone Mediated Autophagy in the Crosstalk of Neurodegenerative Diseases and Metabolic Disorders

Abstract

Chaperone Mediated Autophagy (CMA) is a lysosomal-dependent protein degradation pathway. At least 30% of cytosolic proteins can be degraded by this process. The two major protein players of CMA are LAMP-2A and HSC70. While LAMP-2A works as a receptor for protein substrates at the lysosomal membrane, HSC70 specifically binds protein targets and takes them for CMA degradation. Because of the broad spectrum of proteins able to be degraded by CMA, this pathway has been involved in physiological and pathological processes such as lipid and carbohydrate metabolism, and neurodegenerative diseases, respectively. Both, CMA, and the mentioned processes, are affected by aging and by inadequate nutritional habits such as a high fat diet or a high carbohydrate diet. Little is known regarding about CMA, which is considered a common regulation factor that links metabolism with neurodegenerative disorders. This review summarizes what is known about CMA, focusing on its molecular mechanism, its role in protein, lipid and carbohydrate metabolism. In addition, the review will discuss how CMA could be linked to protein, lipids and carbohydrate metabolism within neurodegenerative diseases. Furthermore, it will be discussed how aging and inadequate nutritional habits can have an impact on both CMA activity and neurodegenerative disorders.

Keywords: CMA; carbohydrates; lipids; metabolism; neurodegeneration.

Figure 1

Chaperone mediated autophagy mechanism. The scheme shows the principal events in CMA mediated translocation of proteins through the lysosomal membrane and known regulatory mechanisms. (A) LAMP-2A exist as an inactive oligomer at the lysosomal membrane. CMA protein substrates containing KFERQ motifs and HSC70 can bind to the cytosolic tail of LAMP-2A with similar affinity. The short C-terminal tail of LAMP-2A exposed to the cytoplasm and conformed by 12 amino acids probably binds to the chaperone and the substrate in a competitive manner. However, on the substrate, binding sites for HSC70 and LAMP-2A do not overlap allowing the HSC70-substrate complexes to interact with LAMP-2A oligomer in a substrate dependent manner. (B) In a dynamic fashion, GFAP favors the formation of high molecular weight aggregates of LAMP2A. Somehow, coupled and simultaneous binding of the substrate to HSC70 and LAMP-2A is sensed by the transmembrane domains of the LAMP-2A for rearrangements in the supramolecular complexes. Next, substrate unfolding and translocation to the lysosomal lumen occurs. A lysosomal-HSC70 (Lys-hsc70) collaborates in this process. (C) A signaling pathway involving phosphorylating and dephosphorylating signals, where AKT, MTORC2, PHLPP1, RAC1, and GFAP, regulate the stabilization of the LAMP-2A complex at lysosomal membranes.

Figure 2

Consequences of downregulated CMA activity. The scheme shows the principal mechanisms of CMA downregulation. Reduced expression of the lamp2 gene has been related with genetic polymorphisms (96), aging (108) and metabolic disorders (132). In relation to the latter situation, HFD has been shown to modify the lipid composition of lysosomal membranes, including increased levels of cholesterol and ceramide (132). These modifications induces the formation of organized lipid microdomains, which prevent LAMP-2A multimerization and stimulate subsequent degradation through proteolysis by Cathepsin D (CatD) (133). Independently of the mechanism, a reduction in CMA activity can induce an increase in the levels of some proteins related with the development of neurodegenerative diseases. In the case of tau, α-synuclein or other less characterized CMA protein substrates that are able to aggregate, increases the total mass that these proteins would contribute to protein oligomerization, an event associated with a blockade of CMA transport. In addition, oxidative damage, would enhance the aggregation process. Additionally, changes in signaling pathways that control LAMP2A oligomerization and membrane stabilization can alter LAMP-2A membrane dynamics and CMA activity. Finally, CMA down-regulation can alter a series of other specific proteins related with neuronal survival or neuroinflammation, that participate in the development of neurodegenerative diseases.

Figure 3

CMA in the crosstalk of metabolic dysfunction and neurodegenerative diseases. Increased caloric intake in humans produces elevated circulating levels of carbohydrates (CHO) and free fatty acids (FFA). In the liver, FFAs accumulate in lipid droplets leading to hepatic steatosis. FFAs also inhibit CMA and lipophagy. The latter contributes to hepatic fat accumulation and systemic dyslipidemia that, together with increased levels of glucose, leads to metabolic syndrome characterized by insulin resistance and diabetes. Metabolic syndrome is a general status also characterized by oxidative stress, inflammation and endothelial dysfunction. This condition is present throughout the body and is also capable of affecting the nervous system, resulting in lipid dyshomeostasis, mitochondrial dysfunction, loss of proteostasis and protein aggregation in the brain. All of these processes have been shown to alter proteostatic mechanisms, including CMA. Loss of neuronal proteostasis finally alters neuronal function which leads to dementia or the development of neurodegenerative diseases.