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  • Alzheimer s disease is the most

    2018-10-23

    Alzheimer\'s disease is the most common progressive neurodegenerative dementia and is characterized by the accumulation of plaques and intra-neuronal fibrillary tangles, where the former consists of beta-amyloid peptides (Aβ) that are highly insoluble and toxic (Querfurth and LaFerla, 2010), and the latter is composed of hyperphosphorylated microtubule-associated protein TAU CA-074 (Wang et al., 2013). Defective lysosomal proteolysis and compromised autophagosome transport occurs in AD resulting in an accumulation of autophagosomes as well as Aβ peptides and Tau protein aggregates (Zhang et al., 2016). Huntington\'s disease is an autosomal dominant disease caused by CAG repeat expansion in the portion of the gene containing several glutamines, known as the polyglutamine (Poly Q) tract of the HTT gene (Novak and Tabrizi, 2010) and patients present with cognitive dysfunction and a loss of motor control thought to be due to toxic aggregates from the polyQ containing protein. Cytoplasmic aggregates formed by mutant forms of HTT (mHTT) can be removed by autophagy, and stimulation of autophagy with mTOR inhibitors, as well as mTOR independent autophagy inducers, can reduce neuronal toxicity in Huntington\'s disease models (Sarkar et al., 2007b) (Table 1). Autophagosomes in HD disease may also be defective and are often devoid of contents resulting in abnormal amounts of mHTT protein aggregates that are not degraded by the lysosome (Martinez-Vicente et al., 2010). Additionally, mHTT itself affects autophagy resulting in accumulation of autophagosomes that are unable to fuse with lysosomes (Wong and Holzbaur, 2014). Accumulation of α-synuclein (SNCA) defines the molecular pathology of Parkinson\'s disease, a progressive disorder that results from the death of dopaminergic neurons in the substantia nigra. Patients accumulate Lewy bodies, intracytoplasmic inclusions containing SNCA, which act as a neurotoxin. Macroautophagy, CMA, as well as mitophagy (i.e. selective autophagy of mitochondria) have all been implicated in PD (Nah et al., 2015; Narendra et al., 2008). Notably, Pink1 and Parkin, two proteins whose loss of function is directly linked to Parkinson\'s disease, also help facilitate the removal of damaged mitochondria by the process of mitophagy, and loss of this process resulting in an accumulation of dysfunctional mitochondria has been shown to be causative for the disease (Rub et al., 2016). Additionally, loss of autophagy results in increased oxidative stress, which exacerbates PD pathology (Surendran and Rajasankar, 2010). In light of these and other studies suggesting that autophagy plays a cytoprotective role against neurodegenerative diseases (Rubinsztein et al., 2015), a number of interventions to enhance autophagic flux, that is the fusion of lysosomes and autophagosomes and degradation of autophagosome cargo, have been tested (Table 1). One study shows that in an animal model of AD, the Vitamin B precursor, Nicotinimide could reduce Aβ and hyperphosphorylated Tau as well as improve cognitive performance, all dependent on restoration of autophagy (Liu et al., 2013). Resveratrol inhibits rotenone-induced dopaminergic neuron cell death in a model of PD (Lin et al., 2014). Because the effects were abrogated by an autophagy inhibitor this is thought to be due to autophagy. mTOR inhibitors such as rapamycin and CCI-779 can induce autophagy to improve motor neuron functioning in fly and mouse models of HD (Ravikumar et al., 2004). Consequently, several compounds including many that feed into mTOR signaling are moving forward towards clinical trials for different diseases (Table 1). One such class of drugs antagonize the G-protein coupled receptor, 5-HT6R, known to activate mTOR signaling in the brain (Meffre et al., 2012), and include the compounds AVN-211 (Ivachtchenko et al., 2016) (Morozova et al., 2014) (Phase IIa clinical trial for Schizophrenia, highlighting safety), Lu AE58054 (AKA idalopirdine)(Wilkinson et al., 2014)(Phase III clinical trial for AD - NCT02006641, NCT02006654, NCT02079246), and SB-742457(Maher-Edwards et al., 2010) (Phase II clinical trial for AD- NCT00224497, NCT0034819, NCT00708552, NCT00710684).