Genetic Determinants of Parkinson's Disease: Can They Help to Stratify the Patients Based on the Underlying Molecular Defect?

Abstract

Parkinson's disease (PD) is a sporadic progressive neurodegenerative brain disorder with a relatively strong genetic background. We have reviewed the current literature about the genetic factors that could be indicative of pathophysiological pathways of PD and their applications in everyday clinical practice. Information on novel risk genes is coming from several genome-wide association studies (GWASs) and their meta-analyses. GWASs that have been performed so far enabled the identification of 24 loci as PD risk factors. These loci take part in numerous cellular processes that may contribute to PD pathology: protein aggregation, protein, and membrane trafficking, lysosomal autophagy, immune response, synaptic function, endocytosis, inflammation, and metabolic pathways are among the most important ones. The identified single nucleotide polymorphisms are usually located in the non-coding regions and their functionality remains to be determined, although they presumably influence gene expression. It is important to be aware of a very low contribution of a single genetic risk factor to PD development; therefore, novel prognostic indices need to account for the cumulative nature of genetic risk factors. A better understanding of PD pathophysiology and its genetic background will help to elucidate the underlying pathological processes. Such knowledge may help physicians to recognize subjects with the highest risk for the development of PD, and provide an opportunity for the identification of novel potential targets for neuroprotective treatment. Moreover, it may enable stratification of the PD patients according to their genetic fingerprint to properly personalize their treatment as well as supportive measures.

Effects of Genetic Variability in Dopaminergic Pathway on Treatment Response in Parkinson’s Disease

“…Furthermore, most of the cohorts included patients with different symptomatology, which may also reflect differences in pathogenesis of PD in these patients, consistent with reports that different cellular defects contribute to development of PD or are even causative of PD [8]. As cohorts in pharmacogenetic studies are so heterogeneous, significant factors that may predict treatment outcome may be overlooked, because they might be relevant only for one particular subgroup of PD patients but not for the others.…”

Biomaterials in Neurodegenerative Disorders: A Promising Therapeutic Approach

“…The incidence of PD is eight to 18 per 100,000 person-years overall, and prevalence reaches 1% in subjects over 60 years and 3% over 80 years with a higher incidence in men than in women [15]. As in other NDs, there are two forms: the sporadic form, which represents 90% of the cases, with an early onset, and the familial form, which represents 10-15% of the cases with an onset beyond 50 years [16,17]. PD is characterized by the degeneration of dopaminergic neurons of the substantia nigra pars compacta, which projects to the basal ganglia and to the striatum [18].…”

Dysregulated Lipid Metabolism and Its Role in α-Synucleinopathy in Parkinson’s Disease

“…The SCARB2 locus was also found to be associated with PD by Simon-Sanchez et al (2009), which was later confirmed by two other genome wide association studies (GWAS) (Do et al, 2011; Nalls et al, 2014). This gene encodes a GCase receptor called lysosomal membrane protein 2 (LIMP-2) which is responsible for directing GCase to lysosomes (Redensek et al, 2017). A deficiency in LIMP-2 can cause a decrease in GCase activity and in the degradation of α-syn (Gan-Or et al, 2015), and could therefore potentially lead to a decrease in ceramide levels, lending yet more support to this hypothesis.…”