Essays On Genetic Mutations

Essays On Genetic Mutations-70
The missense mutation α-synuclein-A53T (Polymeropoulos et al., 1997) was the first gene to be attributed to disease development and its discovery represents a defining moment in PD research, not only preceding the identification of many other genetic determinants of PD but also mechanisms of sporadic disease. Since then, other point mutations in α-synuclein (A30P, E46K, G51D, and H50Q), as well as gene duplications and triplications, have been identified in familial PD (Krüger et al., 1998; Singleton et al., 2003; Zarranz et al., 2004; Appel-Cresswell et al., 2013; Lesage et al., 2013). α-synuclein is a pre-synaptic protein that plays a role in SNARE complex assembly and the exocytosis of neurotransmitters (Burré et al., 2010; Garcia-Reitböck et al., 2010; Bendor et al., 2013).

The missense mutation α-synuclein-A53T (Polymeropoulos et al., 1997) was the first gene to be attributed to disease development and its discovery represents a defining moment in PD research, not only preceding the identification of many other genetic determinants of PD but also mechanisms of sporadic disease. Since then, other point mutations in α-synuclein (A30P, E46K, G51D, and H50Q), as well as gene duplications and triplications, have been identified in familial PD (Krüger et al., 1998; Singleton et al., 2003; Zarranz et al., 2004; Appel-Cresswell et al., 2013; Lesage et al., 2013). α-synuclein is a pre-synaptic protein that plays a role in SNARE complex assembly and the exocytosis of neurotransmitters (Burré et al., 2010; Garcia-Reitböck et al., 2010; Bendor et al., 2013).

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The remaining cases have been attributed to other risk associated genes, environmental exposures and gene–environment interactions, making PD a multifactorial disorder with a complex etiology. doi: 10.1042/bj2660329 Cross Ref Full Text | Google Scholar Gavin, C.

However, enormous efforts from global research have yielded significant insights into pathogenic mechanisms and potential therapeutic targets for PD.

Multiple mitochondrial targeting domains have been identified within the N-terminal domain of the protein and confer its ability to bind to components of the mitochondrial membrane (Devi et al., 2008).

Specifically, α-synuclein can bind to cardiolipin (Nakamura et al., 2008), TOM20 (Di Maio et al., 2016), TOM40 (Devi et al., 2008) and VDAC (Rostovtseva et al., 2015) either to directly promote dysfunction at the membrane level or to allow import into other mitochondrial compartments. Mitochondrial i PLA2 activity modulates the release of cytochrome c from mitochondria and influences the permeability transition.

For this reason, we are making all Reflections articles available as components of this archive, and we look forward to their being collected into a published volume with new commentary in the next year.

Parkinson’s disease (PD) is a devastating neurological movement disorder. Mn2 sequestration by mitochondria and inhibition of oxidative phosphorylation. Environmental factors and gene–environment interactions have been implicated in idiopathic PD. doi: 10.1073/pnas.0802076105 Pub Med Abstract | Cross Ref Full Text | Google Scholar Gavin, C. This neurological disorder is therefore a polygenic disease with various genetic and environmental contributors cumulatively directing its pathological development. Pathological hallmarks of PD include the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of cytoplasmic protein aggregates known as Lewy bodies in remaining dopaminergic neurons (Przedborski, 2017). When degeneration in these neurons results in a threshold reduction of approximately 80% of striatal dopamine, motor symptoms of PD such as rigidity, resting tremor, bradykinesia and postural instability start to emerge (Dauer and Przedborski, 2003). Approximately 30% of the familial and 3–5% of sporadic PD cases are caused by monogenic mutations, while the other remaining cases are classified as idiopathic and sporadic with unknown etiology (Klein and Westenberger, 2012; Hernandez et al., 2016). Duplications are more common than triplications, which has been found in several families (Hernandez et al., 2016). doi: 10.1046/j.1471-4159.1997.69031322.x Pub Med Abstract | Cross Ref Full Text | Google Scholar Gandhi, S., Wood-Kaczmar, A., Yao, Z., Plun-Favreau, H., Deas, E., Klupsch, K., et al. PINK1-associated Parkinson’s disease is caused by neuronal vulnerability to calcium-induced cell death. α-synuclein is also understood to be a key factor of sporadic PD and present in Lewy bodies, which are abnormal proteins commonly observed in PD (Spillantini et al., 1998). Although the majority of α-synuclein is present in the cytosol, the protein also localizes to mitochondria and induces dysfunction (Devi et al., 2008; Parihar et al., 2008; Liu G. et al., 2009; Nakamura et al., 2011; Subramaniam et al., 2014; Chen et al., 2015; Di Maio et al., 2016). The fact that duplications and triplications of SNCA can also cause PD (Singleton et al., 2003) is significant because it indicates that elevated wild type α-synuclein alone is sufficient to cause disease. doi: 10.1016/j.molcel.20 Pub Med Abstract | Cross Ref Full Text | Google Scholar Gan-Or, Z., Amshalom, I., Kilarski, L. So far, A53T has been found in seven families worldwide and only one family for each other four missense mutations. L., Bar-Shira, A., Gana-Weisz, M., Mirelman, A., et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. doi: 10.1212/wnl.0000000000001315 Pub Med Abstract | Cross Ref Full Text | Google Scholar Garcia-Reitböck, P., Anichtchik, O., Bellucci, A., Iovino, M., Ballini, C., Fineberg, E., et al. SNARE protein redistribution and synaptic failure in a transgenic mouse model of Parkinson’s disease. doi: 10.1093/brain/awq132 Pub Med Abstract | Cross Ref Full Text | Google Scholar Gassner, B., Wüthrich, A., Scholtysik, G., and Solioz, M. The pyrethroids permethrin and cyhalothrin are potent inhibitors of the mitochondrial complex I.

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