Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process

Abstract

Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to rare monogenic familial forms of PD with Mendelian inheritance. Biochemical studies revealed that the products of these genes usually play key roles in the proper protein and mitochondrial quality control processes, as well as synaptic transmission and vesicular recycling pathways within neurons. Despite this, large number of patients affected with PD typically tends to show sporadic forms of disease with lack of a clear family history. Recent genome-wide association studies (GWAS) meta-analyses on the large sporadic PD case–control samples from European populations have identified over 12 genetic risk factors. However, the genetic etiology that underlies pathogenesis of PD is also discussed, since it remains unidentified in 40% of all PD-affected cases. Nowadays, with the emergence of new genetic techniques, international PD genomics consortiums and public online resources such as PDGene, there are many hopes that future large-scale genetics projects provide further insights into the genetic etiology of PD and improve diagnostic accuracy and therapeutic clinical trial designs.

Essential Tremor and Parkinson’s Disease: Exploring the Relationship

“…In addition to the over 20 genes identified in such cases, there has increasingly been an identification of risk factor genes, such as GBA , LRRK2 , MAPT , and SNCA in PD patients 106,107. Genetic abnormalities found in sporadic and familial PD have been also evaluated in patients with ET, though without an association thus far.…”

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

“…Recently, variants in other lysosomal genes, even from the same pathway of GBA1 , were also associated with PD susceptibility …”

“…37,38 Recently, variants in other lysosomal genes, even from the same pathway of GBA1, were also associated with PD susceptibility. 9 Single-nucleotide polymorphisms (SNPs) on SCARB2, which encodes for lysosomal integral membrane protein 2 (LIMP-2), a protein responsible for GCase trafficking, have been also shown to be linked to the onset of LB pathologies. 39,40 Although no relevant changes in GCase activities were recently found in dried blood spots of PD patients carrying SCARB2 SNPs versus controls, 41 homozygous mutations are known to be responsible for the onset of lysosomal disorders with a systemic reduction in GCase activity.…”

“…Among the causes of uncontrolled α‐syn accumulation and aggregation, overexpression of α‐syn and failure of cellular protein degradation systems play a major role . Mutations in genes associated to the autophagic‐lysosomal pathway (ALP) are recognized as genetic causes or risks factors for PD onset . Autophagy is a catabolic process in which dysfunctional cytoplasmic components (organelles and proteins) are rerouted toward the lysosomal environment for degradation.…”

“…8 Mutations in genes associated to the autophagic-lysosomal pathway (ALP) are recognized as genetic causes or risks factors for PD onset. 9 Autophagy is a catabolic process in which dysfunctional cytoplasmic components (organelles and proteins) are rerouted toward the lysosomal environment for degradation. Three types of autophagy have been identified based on the pathway by which the substrates reach the lysosomal compartment: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA).…”