Growing evidence supports an active role for deregulated macroautophagy (autophagic stress) in neuronal cell death and neurodegenerative diseases, as Parkinson’s disease (PD). The exact etiology of PD is currently unknown, but it seems clear that its pathogenesis is a multifactorial process. The detection of genetic alterations may be useful as a biomarker of early molecular diagnosis, but it is also important to know and identify changes at the molecular level, more frequent in cases of Parkinsonism. In this sense, the phenomenon of autophagic cell death, described in the normal nervous system, could be the result of a pathological process, such as those related to neurodegenerative diseases. Autophagy is an intracellular catabolic mechanism mediated by lysosomes, which is responsible for most of the degradation and recycling of cytoplasmic components and intracellular organelles dysfunctional or damaged. For a long time, it is unknown why the aggregation of proteins and developmental neurotoxicity are given in a later period of life, even in familial forms of the disease, where the mutant protein is present throughout life in the individual. It has been shown that genetic ablation of autophagy induces neurodegeneration and accumulation of ubiquitinated proteins. In addition, some genetic mutations that cause neurodegenerative diseases directly affect proteolytic systems responsible for the degradation of the mutant protein. In this paper, we analyze the possible neuroprotective role that autophagy-inducing substances can have on the mechanism and development of PD.
2.1. The role of autophagy in PD – Importance of oxidative stress
PD is a progressive neurodegenerative disorder characterized by slow movements (bradykinesia), poverty of movements (hypokinesia), resting tremor and rigidity. PD is characterized pathologically by the loss of dopaminergic neurons in the
While the primary cause of PD in the majority of patients is not known, the number of genetic causes and risk factors are gradually increasing and are beginning to highlight important pathogenetic pathways. The role of mitochondrial dysfunction in PD is supported by the ability of the mitochondrial toxins MPTP (1-methyl-4-phenylpyridinium) and rotenone to target the dopaminergic neurons and more recently by PTEN-induced kinase 1 (PINK1) and parkin, which are mutated in PD and have a role in regulating mitochondrial integrity. Oxidative stress and damage are important observations in PD brains and are common observations in various genetic and toxin models of PD. Protein turnover pathways have been implicated in PD, initially involving the proteasomal system and more recently autophagy and the lysosomal pathways. The
Autophagy is a catabolic pathway for destruction and turnover of long-live proteins and organelles in lysosomes. Autophagy contributes to degradation of damaged long-live proteins and organelles and the normal turn-over of these components, moreover is up-regulated in response to external stressors as starvation and oxidative stress. In mammalian cells autophagy comprises three separate pathways: macroautophagy, microautophagy and chaperone-mediated autophagy (CMA).
Macroautophagy involves the de novo formation of double membrane vacuoles, autophagosomes originated from mitochondria and/or plasma membrane. Autophagosomes fuse with lysosomes to deliver cytoplasmic contents including misfolded or aggregated proteins and organelles for digestion and recycling of amino acids. Macroautophagy is regulated at molecular level by proteins of the Atg family, which form dynamic complexes involved in the assembly, docking and degradation of the autophagosome. The serine/threonine kinase mTOR (mammalian target of rapamicyn) is a key mediator of macroautophagy upregulation under starvation, this protein regulates cell cycle progression, protein synthesis and cell growth. Activated mTOR promotes protein synthesis and inhibits catabolism by decreasing macroautophagy in a mechanism mediated by Atg13 phosphorylation that modulates Atg1 activity. During starvation mTOR is inactivated resulting in hypophosphorylation of Atg13 and stimulation of Atg1-Atg13 complexes required for induction of autophagy.
Microautophagy involves lysosomal pinocytosis of cytoplasmic contents and is involved in the turnover of long half-life cytosolic proteins. However, the underlying process is poorly understood in mammalian cells.
It is important to note that both macro and microautophagy are highly conserved process that occurs in same manner in all cells. In this sense most of the knowledge of autophagy was first described in yeast.
CMA is a selective autophagic pathway dependent upon the protein chaperone hsc70 and its binding to LAMP-2A (Lysosomal-associated membrane protein 2A), a lysosomal surface receptor. A highly specific subset of cytosolic proteins with a KFREQ motif are recognized by the hsc70 chaperone and internalized for degradation by Lysosomal-associated membrane protein 2A LAMP-2A lysosomal membrane receptors. The substrate protein is unfolded by the complex and is translocated to the lysosome with the help of a lysosomal chaperone (lys-hsc70).
Recent reports identified a increase in autophagic vacuoles, decrease in macroautophagy and CMA proteins in PD brain areas affected by the neurodegenerative process, which might have a direct impact in alpha-synuclein levels as this protein in degraded in lysosomes mainly by CMA. The increase cytosolic alpha-synuclein levels favours the modification of alpha-synuclein and formation of oligomers, fibrils and aggregates. Indeed, CMA is important in the removal of oxidized and altered proteins during conditions of mild oxidative stress, and blockage of CMA resulted in increased intracellular levels of oxidized and aggregate proteins. Conversely the pathological environment in PD may lead to alpha-synuclein post-translational modifications (e.g. nitration, oxidation, dopamine adducts), or oligomeric or fibrilar formations which may not be degraded by CMA and may even inhibit CMA promoting aggregation. Moreover, mutations in PINK1 and parkin proteins, associated with PD, affect the remove of damaged mitochondria by lysosomes (mitophagy). Finally, other genetic mutations associated with PD, as ATP13A2 and LRRK2, affect autophagy and lysosomal function, reinforcing the involvement of autophagic function in PD.
Several studies described an increase in markers related with oxidative stress as protein nitration and lipid peroxidation in LB. Additional findings described a decrease in several defense antioxidant molecules in PD including the thiol-reducing agent glutathione (GSH) and the glutathione peroxidase activity. This increase in reactive oxygen species (ROS) levels involves an increased oxidized alteration of proteins as alpha-synuclein resulting in increasing protein misfolding and impaired degradation, which might cause the accumulation of toxic soluble oligomers or insoluble aggregates.
Mitochondria are the main source of ROS involved in oxidative stress and its role in PD is highlighted by the toxic animal models (MPTP, 6-hydroxydopamine (6-OHDA), rotenone) and the mutation in PINK1, parkin and DJ-1, involved in mitochondrial function and turnover, is related with early onset PD. When oxidative processes clearly contribute to the pathology and progression of PD the initiation of this cascade is probably secondary to other causes.
2.2. Toxic stress inducers related to PD
2.3. Enhancers of autophagy as neuroprotectors in PD
Autophagy is involved in stress-induced adaptation as well as cellular development, differentiation and survival. Regulation of autophagy determines the fate of cells in multiple organs. One of the main concerns of autophagic regulation is the significance of cell-type or tissue specificity. Specifically, neurons could be vulnerable to an accumulation of abnormal components such as cytosolic proteins or organelles that are damaged regarding their post-mitotic nature. Therefore, the regulation of neuronal autophagy in a healthy or diseased environment is most likely context-dependent. Neurons differ from other cell types in that they are post-mitotic and highly dependent on the endo-lysosomal pathway for active signaling in the axons and dendrites. Due to these features, neurons require effective protein degradation as a quality control for cell survival, especially under disease conditions for the removal of toxic components. Any alteration of protein degradation can cause the accumulation of abnormal proteins, leading to cellular toxicity and ultimately neurodegeneration. In this sense, increasing evidences suggest that autophagic deregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as PD. A viable therapeutic strategy might be to reduce the accumulation of the toxic protein in the cytoplasm. Indeed, promoting the clearance of aggregate-prone proteins via pharmacological induction of autophagy has proved to be a useful mechanism for protecting cells against the toxic effects of these proteins. An additional benefit of autophagy upregulation in models of neurodegenerative diseases is that it seems to protect cells against apoptotic insults. Some evidence also indicates that autophagy might protect cells against necrotic cell death, although this mechanism has not been studied in the context of neurodegeneration. Therapeutic approaches that promote autophagy could, therefore, have two beneficial effects in the context of neurodegenerative diseases; first, they might improve the removal of toxic aggregate-prone proteins from neurons, and second, they could protect neurons from apoptosis.
Autophagy enhancers can be classified in two groups, mTOR dependent and mTOR independent. For this review we will focus in the second.
3. Conclusions and future perspectives
Future studies may focus on identifying specific molecules that modulate each step in the autophagy pathway. Small molecules and pharmacologic agents that can more selectively modulate certain aspects of autophagic stress may also help usher in the first wave of disease-specific therapies. Ideally, small molecule regulators would affect only certain aspects or targets of the autophagy pathway, since global inhibition or enhancement of protein turnover could be problematic. In situations with substantial aggregation, however, a global induction of autophagy may be required provided this does not outstrip the degradative capacity of the aged or diseased cell. Promoting expression of biomolecules required for both induction and clearance of autophagosomes may serve to prevent potential autophagic stress. To determine the mechanism of the possible neuroprotective role of autophagy in PD would provide, eventually, the design of therapeutic interventions (drugs or cell therapy) for treatment of patients affected by this disease.
4. Funding sources
Dr. Rosa A. González-Polo received research support from ISCIII (Ministerio de Economía y Competitividad, Spain (CP0800010, PI11/0040) and FUNDESALUD (PRIS11014). Dr. José M. Fuentes received research support from the ISCIII (Ministerio de Economía y Competitividad, Spain (PI12/02280), FUNDESALUD (PRIS11019), CIBERNED (CB06/05/004) and Consejería, Economía, Comercio e Innovación, Junta de Extremadura (GRU10054). Mireia Niso-Santano was supported as a postdoctoral researcher by the University of Extremadura. Rosa A. González-Polo was supported by a “Miguel Servet” contract (ISCIII, Ministerio de Economía y Competitividad, Spain). Elisa Pizarro-Estrella is supported by a predoctoral contract from CIBERNED. Jose M Bravo San-Pedro and Ruben Gómez-Sánchez are beneficiaries to fellowship from Univesity of Extremadura and Minister of Economia y Competitividad respectively.
The following abbreviations were used in this paper:
PD, Parkinson´s disease; CBZ, carbamazepine; LB, Lewy bodies; LAMP-2A, Lysosomal-associated membrane protein 2A; LRRK2, Leucine-rich repeat kinase 2; PINK1, PTEN-induced kinase 1; CMA, chaperone-mediated autophagy; mTOR, mammalian target of rapamicyn; FKBP12, FK506-binding protein of 12 kDa; AMPK, 5'-adenosine monophosphate-activated protein kinase; MPP+, 1-methyl-4-phenylpyridinium; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PQ, paraquat;
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