Parkinson's Disease (PD)

Overview

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and is the most prevalent movement disorder of mysterious etiology. PD is rare before the age of 50, but its prevalence increases with age affecting more than 1% of the population over the age of 60 and ~4% at the age of 80 years. It is characterized clinically by a classic tetrad of motor symptoms: low frequency resting tremor, slowness of movement (bradykinesia), and postural instability.

Neuropathologically, PD is defined by the loss of dopaminergic neurons in the substantia nigra pars compacta. It is associated with eosinophilic, intracellular proteinaceous inclusions, termed Lewy bodies, and dystrophic Lewy neurites in the brain stem and cortical areas. The essential components of these inclusions are a-synuclein, neurofilament proteins, and ubiquitin. In addition, gliosis is observed in the striatum and the substantial nigra of PD patients.

Fig.1 Anatomy and physiology of PD motor manifestations. (Shulman, 2011)

Genetic Risk Factors for HD

PD is an excellent example of the power of molecular genetics to understand a human condition. The genetic studies of the past few decades have revolutionized the PD research field and primed the development of innovative theories for its pathogenesis. It becomes increasingly clear that genetic factors contribute to the complex pathogenesis of PD. The knowledge acquired of the functions of their proteins has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. Many associated genes have been identified for dominant and recessive diseases that have many characteristics of PD. These include some autosomal dominant genes, α-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2) and VPS35, and three autosomal recessive genes, Parkin, DJ-1, and PTEN-induced putative kinase 1 (PINK1).

• Autosomal Dominant Forms of PD

The identification of mutations in the SNCA gene, causing rare inherited forms of the disease, led to the discovery of the α-synuclein protein as the main component of Lewy bodies (LBs). Misfolding and aggregation of the a-synuclein protein into neurotoxic species and cell-to-cell spread are at the center of the current pathogenetic theories for PD. Patients with SNCA missense mutations or multiplications often show dementia as an additional key feature and present with atypical characteristics such as pyramidal signs, myoclonus, or seizures.

Mutations in another gene, LRRK2, are the most frequent cause of PD and are likely to play a role in the typical sporadic late-onset disease setting, but how does this fit into the α-synuclein cascade remain unknown. LRRK2 mutations explain up to ~10% of the PD patients with familial, autosomal dominant inheritance. Some groups report that the heterozygous mutations in the GBA gene are strong risk factors for PD and diffuse Lewy-body disease (DLB). The patients with GBA pathogenic mutations have typical PD with possibly a slightly earlier onset age.

Fig.2 Neuropathology of PD. (Dauer, 2003)

• Autosomal Recessive Forms of PD

Mutations in the following three genes: parkin (PRKN, PARK2), PTEN induced putative kinase 1 (PINK1, PARK6), and Parkinson protein 7 (DJ-1, PARK7) can cause autosomal recessive forms of early-onset parkinsonism, usually without atypical clinical signs. While mutations in these genes are all relatively rare in the general PD population, they are responsible for a substantial proportion of early-onset PD. Notably, recessive parkinsonism has been implicated in a common pathway of mitochondrial quality control. Mutations in another two genes, DNAJC6 and SYNJ1, were identified as the cause of autosomal recessive juvenile parkinsonism. Parkin-linked PD may give rise to a broad range of clinical phenotypes but generally causes early-onset parkinsonism, slow progression, L-dopa responsiveness, and occasional early-onset dystonia.

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References

1. Shulman, J. M.; et al. Parkinson's disease: genetics and pathogenesis. Annual Review of Pathology: Mechanisms of Disease. 2011, 6, 193-222.
2. Dauer, W.; Przedborski, S. Parkinson's disease: mechanisms and models. Neuron. 2003, 39(6), 889-909.