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).
Since the identification of the first missense substitution in SNCA (Polymeropoulos et al., 1997), the gene encoding α-synuclein, the understanding of the genetic contribution to PD has progressed rapidly and has become rather complex.
In addition to the emergence of multiple loci as causative factors in familial PD (Table 1), genome wide association studies (GWAS) and Genome-wide complex trait analysis (GCTA) have uncovered a significant genetic component to the idiopathic disease (Hernandez et al., 2016; Przedborski, 2017).
This review will discuss the impact of genetic mutations, environmental toxicants and gene–environment interactions on PD pathogenesis. doi: 10.1186/1750-1326-7-22 Pub Med Abstract | Cross Ref Full Text | Google Scholar Gautier, C.
Furthermore, we will highlight mitochondria as a common target for both genes and environmental toxicants linked to PD.
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.
Although mutations in these genes alone may not be considered as causative, they significantly increase the risk of developing idiopathic PD.
This is, at least in part, due to incomplete and variable penetrance of the majority of these mutations.
This review will highlight mitochondrial dysfunction as a common pathway involved in both genetic mutations and environmental toxicants linked to PD.
Parkinson’s disease (PD), characterized by degeneration of the nigrostriatal dopaminergic pathway, is the second most prevalent neurodegenerative disorder after Alzheimer’s disease. Manganese and calcium efflux kinetics in brain mitochondria.