Parkinson's disease: insights from pathways

Abstract

Parkinson's disease (PD) typically presents in sporadic fashion, but the identification of disease-causing mutations in monogenically inherited PD genes has provided crucial insight into the pathogenesis of this disorder. Mutations in autosomal recessively inherited genes, namely parkin, PINK1 and DJ-1, typically lead to early onset parkinsonism. At least two of these genes (PINK1 and parkin) appear to work in the same pathway related to maintenance of mitochondrial functional integrity under conditions of oxidative stress. Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) and alpha-synuclein cause late onset PD, generally with Lewy bodies that are characteristic of sporadic PD and there is evidence that these two genes are also in a common pathway. There is also growing evidence from recently undertaken genome-wide association studies that naturally occurring sequence variants in alpha-synuclein and LRRK2, but also Tau, also confer an increased risk for late onset, sporadic PD. Collectively, these results highlight how understanding pathways for inherited PD are starting to impact ideas about the pathogenesis, some of which may also be relevant to the commoner sporadic disease.

Figure 1.

Genes associated with autosomal recessive early onset parkinsonism. The DJ-1, PINK1 and parkin proteins are drawn approximately to scale, with pathogenic mutations listed above each diagram. DJ-1 is a single domain protein with a critical Cysteine residue (C106) that can be modified in the presence of reactive oxygen species (ROS) to form a sulfinic acid, as indicated. PINK1 contains a mitochondrial targeting sequence (MTS) and a putative transmembrane (TM) region that directs the kinase domain to the outer face of the mitochondria, as well as a C-terminal tail of uncertain function. Parkin is structured with a ubiquitin-like (Ubl) domain at the N-terminus followed by three RING finger domains (R0–R2 for historical regions) separated by an in between RING (IBR) domain, each of which bind two Zn²⁺ atoms. For all three genes, there whole exon deletions and duplications that result in loss of protein as well as point mutations that either destabilize or otherwise functionally inactivate the proteins.

Figure 2.

Genes associated with dominant Lewy body diseases. α-Synuclein and LRRK2 are shown, not to scale, with pathogenic mutations above the protein organization in red. α-Synuclein has a series of imperfect repeats of the general sequence KTEGV and a central hydrophobic NAC (non-amyloid component) region. This is followed by a C-terminal acidic tail. As well as three point mutations, which are in the repeat region, whole gene multiplications have been reported. LRRK2 is a much larger protein that contains LRRK, Ankyrin (ANK) and Leucine-rich repeats (LRR). A catalytic core of the protein contains a GTP-binding ROC (Ras of complex proteins), COR (C-terminal of ROC) and kinase domains. At the C-terminus is a WD40 repeat followed by a short C-terminal tail.