Essays On Genetic Mutations
The emergence of genetic risk factors for cases of idiopathic PD raises an important question: What is causing the increased susceptibility to the disease in individuals that carry these mutations? One possible and particularly pertinent explanation is that risk factor mutations render the individual more sensitive to the pathological influence of environmental factors thus bringing the idea of gene–environment interactions to the forefront. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. articles give insight into fundamental questions in current mutation research.The feature considers mutation as broadly as possible, including its evolutionary, toxicological, medical, statistical, and public policy dimensions, as well as the basic genetics and molecular biology that form the core of mutation research.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). 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 pathology of α-synuclein is largely due to its propensity to aggregate; gradually transitioning from small soluble oligomers to larger insoluble fibrils, ultimately forming Lewy bodies. M510845200 Pub Med Abstract | Cross Ref Full Text | Google Scholar Gainetdinov, R.
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).
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.
α-synuclein-associated mechanisms have therefore been at the forefront of the PD research and multiple high profile discoveries have greatly contributed to the understanding of disease pathology. Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter.
For example, as discussed below, the discovery that α-synuclein pathology can spread from one cell to another in a prion-like fashion has provided a key insight into how PD may develop and provide novel therapeutic strategies.