THE ROLE OF AUTOPHAGY IN DEGENERATIVE DISEASE
Autophagy is a well-developed intracellular breakdown mechanism. Based on the mechanism of cargo transport into lysosomes used by mammals, there are three types of autophagic processes: chaperone-mediated autophagy, microautophagy, and macroautophagy, all of which are referred to as autophagy. Autophagosomes are double-membrane-bound vesicles that absorb unnecessary or misfolded proteins as well as damaged subcellular organelles and transport them to lysosomes for disintegration.
The mammalian target of rapamycin complex 1 (mTORC1), a critical regulator of autophagy, inhibits autophagy at a low baseline level in almost all cells to maintain cellular homeostasis. When mTORC1 is inhibited, autophagy is released in response to many types of cellular stress, such as food restriction, growth factor withdrawal, or hypoxia, and it is greatly increased to meet high energy demands.
Dynamic interactions between compartments of the autophagic and endocytic pathways are essential for digestion to be completed. As the brain ages, neuron interactions become more prone to irregularities. Autophagy-controlling gene alterations have been associated to a wide spectrum of neurodegenerative illnesses in persons of all ages, which is not surprising. Defects in the autophagy system are seen at various stages in late-onset disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and familial Parkinson's disease, with varying etiology and therapeutic implications.
In Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), pathological aberrant protein aggregates cause neurofibrillary illness (ALS). In Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Huntington's disease (HD), pathological aberrant protein aggregates cause neurofibrillary illness (HD). The autophagy-lysosome breakdown mechanism is largely targeted by these protein aggregates prevalent in neurodegenerative diseases. Genetic alterations in autophagic receptors including p62, OPTN, NBR1, and ALFY/WDFY3 have also been linked to neurological diseases.
Aging, the most common risk factor for neurodegeneration, significantly reduces autophagic activity. As a result, it is hypothesized that defective autophagy plays a role in the development of neurodegenerative disorders. Several recent studies suggest that modulating autophagy may be a promising treatment option for certain diseases. Autophagy activation increased the clearance of aggregate-prone proteins such as mHtt, insoluble tau, and A42 and was dependent on the aggrephagy receptor. In contrast, autophagy inhibition with 3-MA or bafilomycin A1 (Baf. A1) increased mHtt aggregates in cell culture systems and rat brains.
Alzheimer's Disease (AD)
Alzheimer's disease (AD) is the most common neurodegenerative illness that causes dementia. The accumulation of Ap plaques and tau neurofibrillary tangles in the brain of Alzheimer's patients is a pathological feature of the illness and a critical aspect of its etiology. Apis a short peptide generated from the sequential processing of APP and is a fundamental component of amyloid plaques. The activation of a-, P- and Y-secretase sequentially cleaves APP into the TGN and endosomes. Autophagy is primarily responsible for the removal of A and APP-CTF. Increased p62 or transcription factor EB (TFEB) activity has been demonstrated to reduce AP plaque development, resulting in an improvement in AD patency.
Increased AP oligomers, on the other hand, inhibited autophagic activity in animal models via impairing trafficking and lysosome biogenesis. Due to lysosomal proteolysis problems, cathepsin-containing autolysosomes accumulated in the brains of Alzheimer's patients, according to ultrastructural studies. Furthermore, autophagy-related protein levels in AD patients' samples are commonly altered.
Several mutations that cause familial Alzheimer's disease have been connected to autophagy. Presenilin 1 (PSEN1/PS-1) is a component of the -secretase complex, which is in charge of A peptide synthesis. PSEN1 genetic mutations have been linked to AD pathogenesis and have been shown to impede APP processing. According to multiple loss-of-function studies, PSEN1 is required for lysosomal homeostasis and transcription of autophagy-related genes. PSEN1 mutations induce familial Alzheimer's disease by causing aberrant v-ATPase trafficking to lysosomes, which results in lysosomal alkalinization and the buildup of faulty autolysosomes. PSEN1-deficient neural stem cells are also found.
Several single nucleotide polymorphisms (SNPs) and abnormal cleaved forms of phosphatidylinositol-binding clathrin assembly protein (PICALM) have been reported in Alzheimer's disease. PICALM is a clathrin adaptor protein involved in SNARE and APP endocytosis via clathrin. During endocytosis, PICALM and APP colocalize, and genetic PICALM downregulation lowers APP endocytosis and plaque development in mouse brains. PICALM is implicated in several phases of the autophagic pathway, according to current research, regardless of its role in APP endocytosis. PICALM controls autophagosome growth and maturation by regulating the endocytosis of SNAREs such as VAMP2, VAMP3, and VAMP8 131. The fusion of autophagosomes and lysosomes is known to be mediated by SNAREs. In combination with adaptor protein 2, PICALM also acts as an autophagic receptor. (AP-2). For autophagic degradation, the AP2-PICALM complex joins the APP-CTF and LC3B proteins.
Beclin-1 and VPS35, a crucial retromer component, may also play a role in autophagy activity in Alzheimer's disease. Beclin-1 and VPS35 levels are reduced in Alzheimer's patients. In mice, genetic downregulation of Beclin-1 led in decreased neuronal autophagy and A accumulation, leading in neurodegeneration. Beclin-1 regulates APP trafficking from the cell surface to autophagosomes via an evolutionarily conserved area that interacts directly with APP (ECD). Beclin-1 influences phagocytosis in neurons via altering the amounts of the VPS35 protein. When VPS35 is knocked off in culture cells, A accumulates.
Autophagy and Huntington Disease
HD is the most common polyglutamine disorder and a dreadful autosomal dominant neurological ailment. Polyglutamine (poly Q) expansions and pathogenic aggregation, both of which are hallmarks of Huntington's disease (HD), are caused by the CAG repeat trinucleotide in the first exon of the huntingtin (HTT) gene (Imarisio et al., 2008; Jimenez-Sanchez et al., 2017). Despite the fact that HD pathogenesis has no effect on autophagosome formation, autophagosomes clumped together in HD (68). Despite the fact that HD pathogenesis has no effect on autophagosome formation, autophagosomes clumped together in HD mice.
Autophagosome trafficking necessitates the presence of huntingtin. Huntingtin loss results in abnormal p62/SQSTM1 expression, which may diminish TDP-43 aggregation in vitro via autophagy or the proteasome (Brady et al., 2011). Several investigations have also discovered a relationship between the disease and the serine/threonine kinase TANK-binding kinase 1. (TBK1) (Kim et al., 2017). A recent study found that TBK1 is an upstream regulator of the autophagy receptor optineurin (OPTN).
A deadly autosomal dominant neurodegenerative condition is the most common polyglutamine disease. The presence of a CAG repeat trinucleotide in the first exon of the huntingtin (HTT) gene causes polyglutamine (poly Q) expansions and pathogenic aggregation in HD.
Despite the fact that HD pathogenesis has no effect on autophagosome production, aggregated autophagosomes have been seen in HD models. Huntingtin is required for the trafficking of autophagosomes. Huntingtin deficiency causes abnormalities in HD models. Mitophagy is aided by both TBK1 and OPTN (Wong & Holzbaur, 2015). Because mitochondria are crucial not just for energy production but also for cellular apoptosis, removing damaged mitochondria is critical for cellular homeostasis. These findings point to mitophagy as a possible new etiology of the condition. Ubiquilin2 (UBQLN2), a proteasome shuttle factor, is necessary for autophagosome formation. In mouse models, UBQLN2 mutations produce cognitive impairments, shortened longevity, and neuron loss. A detailed representation of autophagic flux alterations in neurodegenerative diseases. In HD cell models, rapamycin lowers huntingtin accumulation and cell death. Lithium may be able to prevent cell death in some circumstances.
Trehalose has been demonstrated to bind to expanded polyglutamine and decrease disease progression in HD mice models. Rilmenidine may promote autophagy in cell models (Rose et al., 2010), allowing mutant huntingtin fragments to be eliminated via a mTOR-independent process. Lithium has the ability to decrease mutant huntingtin protein aggregation and cell death. Autophagy and Parkinson's Disease
This is one of the most common diseases categorized as a neurodegenerative disease. Parkinson's Disease (PD) involves the loss of dopamine neurons that happens in the substantia nigra pars compacta (Dauer & Przedborski, 2003). The inclusions of Lewy neurites and Lewy body intercellularly with the compositions of polyubiquitinated proteins and a -synuclein also leads to the Parkinson's Disease. This has been shown by analyzing brain samples of patients suffering from the disease. From these samples it is clear that there is always accumulation of autophagosomes and presence of dysfunctional lysosomes in neurons (Dehay et al., 2010). This highlights that autophagy plays a pathogenic role in patients suffering from Parkinson's disease. The main composition of the Lewy bodies is aggregated and misfolded a -synuclein (Dauer & Przedborski, 2003; Kalia et al., 2013).
The levels of a -synuclein increases when there is an inhibition of lysosome, which indicates a correlation between autophagy and the degradation of a -synuclein. Previous research works have highlighted that autophagy can degrade basically all types of a -synuclein (Dehay et al., 2010; Lee et al., 2004). Proteasome can also degrade monomeric a -synuclein (Webb et al., 2003) which further shows the role that autophagy plays in PD. A significant modulator for autophagy, Transcription factor EB (TFEB) (Settembre et al., 2011), has been determined that it relieves pathology of almost all neurodegenerative diseases. Prevention or reduction of damage of lysosome can be done by over-expressing TFEB. This is because it induces its biogenesis which leads to the ameliorating of the pathology of the a -synuclein (Decressac et al., 2013; Kilpatrick et al., 2015). Therefore, there is a strong indication that autophagy plays a vital part in preventing and treating synucleinopathy in Parkinson's Disease.
Leucine rich repeat kinase 2 (LRRK2) mutations are one of the leading causes of the autosomal dominant type of Parkinson's Disease (Vekrellis et al., 2011). When LRRK2 G2019S is over-expressed in differentiated SHSYGY cells can lead to the shortening of dentric and aggregation of autophagosomes (Plowey et al., 2008). Autophagic flux can be impaired by up- regulating LRRK2 G2019S when a person is aging (Saha et al., 2015). The mutation of VPS35 D620N that results in the dominant autosomal Parkinson's Disease, can destabilize the WASH complex. This can result to defection of the autophagosome formation and this also comprises autophagy protein ATG9 trafficking (Zavodszky et al., 2014).
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- Joseph Kariuki (Autor:in), 2020, The Role of Autophagy in Degenerative Diseases, München, GRIN Verlag, https://www.grin.com/document/1185314