Understanding the molecular causes of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease that is both common and incurable. The majority of cases are sporadic and of unknown origin but several genes have been identified that, when mutated, give rise to rare, familial forms of the disease. The principal genes that have been shown to cause PD are α-synuclein (SNCA), parkin, leucine-rich repeat kinase 2 (LRRK2), PTEN-induced putative kinase 1 (PINK1) and DJ-1. Here, we discuss what has been learnt from the study of these genes and what has been elucidated of the molecular pathways that lead to cell degeneration. Of importance is what these molecular events and pathways tell scientists of the common sporadic form of PD. Although complete knowledge of these genes’ functions remains elusive, recent work implicates abnormal protein accumulation, protein phosphorylation, mitochondrial dysfunction and oxidative stress as common pathways to PD pathogenesis.

Introduction

Parkinson's disease (PD), which was first described by James Parkinson in 1817, is the second most-prevalent neurodegenerative disorder in the Western world. It is characterized by depigmentation of the substantia nigra (SN) – caused by the selective and progressive loss of dopaminergic (DA) neurons – and the presence of intraneuronal proteinaceous inclusions known as Lewy bodies (LBs) (see Glossary) within the surviving neurons of the SN and other brain regions. These inclusions are enriched in filamentous α-synuclein and other proteins that are often highly ubiquitinated. In addition to the loss of ∼50% of neurons in the SN, there is an accompanying pallor of the locus coeruleus (LC). Depletion of dopamine within the striatum causes dysregulation of the motor circuits that project throughout the basal ganglia, resulting in the clinical manifestations of PD. These include slowness of movement (bradykinesia), muscular rigidity, resting tremor and postural instability. Symptoms can be at least partially alleviated by the administration of an exogenous dopamine precursor l-3,4-dihydroxyphenylalanine (l-dopa).

The percentage of affected individuals within a population rises from ∼1% at 65 years to ∼5% at 85 years, making age the main risk factor for PD. The majority of cases are thought to be idiopathic. However, in ∼5–10% of cases, PD is thought to have a genetic component, showing both recessive and dominant modes of inheritance. Until the recent advances in the identification of some of the genes that underlie rare familial forms of the disease, little was known about the molecular pathogenesis of PD.

Linkage data has identified ten loci, named PARK (11 loci were reported until PARK4 has been shown to be a form of SNCA, which was previously called PARK1); six of the genes with pathogenic mutations have now been identified (Table 1). These include two autosomal dominant genes, α-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2), and three autosomal recessive genes, parkin, DJ-1 and PTEN-induced putative kinase 1 (PINK1). The 6th gene, ubiquitin carboxyl-terminal esterase L1 (UCHL1, previously known as PARK5), has only been found in one small family, and its importance in familial PD is still uncertain. There are four remaining loci (PARK3, PARK9, PARK10 and PARK11) for which linkage has been identified; however, the causative genes have not yet been discovered.

Although there are differences between some of the clinical and pathological features observed in familial and non-familial forms of PD, there are sufficient similarities to enable intriguing and relevant insights to be made about the pathogenesis of PD. Moreover, identification of novel targets for the treatment of idiopathic PD (by far the most-common form) is urgent. It is therefore important to characterize these proteins in terms of normal physiological function and dysfunction in disease. Although the precise mechanisms remain unclear, key factors are already strongly implicated in the disease process of both inherited and sporadic PD, including mitochondrial dysfunction, protein phosphorylation, oxidative stress, protein misfolding and impairment of the ubiquitin proteasome system (UPS).