Pathogenesis And Endocytosis

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The proposed mechanism is that the mutated α-synuclein binds directly to the ER-Golgi SNARE complex inhibiting its assembly (Gitler et al., 2008). Altering vesicle trafficking at any point inside the cell can lead to an accumulation of proteins, which can have severe consequences for dopaminergic neurons. The endocytic pathway is also important in the pathogenesis of Prkinson’s disease. Mutations in the cyclin G associated kinase (GAK) are important for endocytosis. Single nucleotide polymorphisms (SNPs) have actually been identified that can be associated with risk factors for sporadic Parkinson’s disease (Nalls et al., 2014). A relationship between one GAK SNPs and increased levels of the protein α-synuclein has been demonstrated on a …show more content…

It is possible that α-synuclein causes the ER stress by interrupting the vesicular protein trafficking and causing the ER to be overworked. It is also found that mutations in the parkin gene end up forming aggregations of its own substrates in the ER, which leads to stress and death of dopamine neurons (Imai et al., 2001). Other than the stress on the ER created by clusters of incorrectly folded α-synuclein proteins, mitochondria that are functioning improperly can also induce stress on the ER. Parkin is an E3 ubiquitin ligase responsible for regulating many cellular processes by tagging proteins with ubiquitin for their destruction (Dawson and Dawson 2010). A loss of function mutation in the parkin gene is seen to play a major role in altering the function of mitochondria leading to stress on the ER (Bouman et al., 2011). Mutations in PINK1 (PTEN induced putative kinase 1) affect pakin translocation and cause mitochondria to accumulate which increases the vulnerability of dopamine neurons (Song et al., 2013). Along with this, muations in both the parkin gene and PINK1 cause ER stress by increasing contacts between ER and dysfunctional mitochondrial, which can lead to neurodegeneration (Celardo et al., 2016). In rare forms of heredity Parkinson’s disease, mutations in

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