Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system

Abstract

Parkinson's disease is a progressive neurological disorder, characterized by prominent movement dysfunction. The past two decades have seen a rapid expansion of our understanding of the genetic basis of Parkinson's, initially through the identification of monogenic forms and, more recently, through genome-wide association studies identifying common risk variants. Intriguingly, a number of cellular pathways have emerged from these analysis as playing central roles in the aetiopathogenesis of Parkinson's. In this review, the impact of data deriving from genome-wide analyses for Parkinson's upon our functional understanding of the disease will be examined, with a particular focus on examples of endo-lysosomal and mitochondrial dysfunction. The challenges of moving from a genetic to a functional understanding of common risk variants for Parkinson's will be discussed, with a final consideration of the current state of the genetic architecture of the disorder. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Keywords: Parkinson's disease; endo-lysosomal; functional genomics; genome-wide association.

Figure 1.

Endo-lysosomal pathways and monogenic Parkinson's disease. Parkin and Pink1 (PRKN and PINK1) play a central role in mitochondrial quality control. LRRK2 and α-synuclein (LRRK2 and SNCA) have been implicated in the regulation of macroautophagy, with LRRK2 also linked to vesicle trafficking at the trans-Golgi and lysosomal damage response. Glucocerebrosidase and ATP13a2 (GBA1 and ATP13a2) have roles in maintaining lysosomal function. Auxilin (DNAJC6) acts to uncoat clathrin-coated vesicles during clathrin-mediated endocytosis.

Figure 2.

A Manhattan plot for genome-wide associated variants in Parkinson's disease, showing –log₁₀p for single nucleotide polymorphisms across the autosomes. The horizontal dotted lines indicate the corrected thresholds for achieving genome-wide significance, with example candidate genes for loci discussed in this review indicated [68].

Figure 3.

The SNCA locus on chromosome 4 and genome-wide associated single nucleotide polymorphisms. Data are derived from the Meta Five genome-wide association analysis, and accessed through the IPDGC genome browser [77].

Figure 4.

The chromosome 7p15.3 locus and GPNMB. Significant single nucleotide polymorphism (SNPs cover a range of genes, including NUPL2, KLHL7 and GPNMB. The most significant SNP is located in a GPNMB intronic region. Data are derived from the Meta Five genome-wide association analysis, and accessed through the IPDGC genome browser [77].

Figure 5.

The chromosome 16q11.2 locus and KAT8. The signal at 16q11.2 covers multiple genes, including SETD1A, which was originally nominated as the lead single nucleotide polymorphism, and KAT8, which has been nominated through functional cell-based screening. Data are derived from the Meta Five genome-wide association analysis, and accessed through the IPDGC genome browser [77].

Figure 6.

Endo-lysosomal pathways and genes implicated by genome-wide association studies for Parkinson's disease. KAT8 and KANSL1 (KAT8 and KANSL1) have been implicated in the regulation of mitochondrial quality control through mitophagy. As for monogenic associations, LRRK2 and α-synuclein (LRRK2 and SNCA) have been implicated in the regulation of macroautophagy, with LRRK2 and Rab29 (RAB29) also linked to vesicle trafficking at the trans-Golgi and lysosomal damage response. Glucocerebrosidase (GBA1), cathepsin B (CTSB), GPNMB (GPNMB) and TMEM 175 (TMEM175) are all linked to catabolic lysosomal function. Finally, GAK (GAK) plays an analogous role to DNAJC6 in uncoating clathrin-coated vesicles.

Figure 7.

The emergent genetic architecture of Parkinson's disease, showing monogenic and genome-wide associated loci. Odds ratios and population frequencies are derived from the IPDGC genome browser [77].