Rare genetic mutations shed light on the pathogenesis of Parkinson disease

Abstract

Parkinson disease (PD) is the second most common pro- gressive neurodegenerative disorder, with a prevalence of approximately 1% at the age of 65, increasing to 4–5% by the age of 85 (1, 2). PD patients suffer from bradykine- sia, tremor, cogwheel rigidity, and postural instability. PD is due to the relatively selective loss of dopaminergic neurons in the substantia nigra pars compacta, which leads to a profound reduction in striatal dopamine (DA). Lewy bodies and dystrophic neurites (Lewy neurites) accompany the loss of dopaminergic neurons (3). Lewy bodies are a pathologic hallmark of PD and classically are round eosinophilic inclusions composed of a halo of radiating fibrils and a less defined core. Both Lewy bod- ies and Lewy neurites are comprised of cytoplasmic accu- mulations of aggregated proteins (3). PD represents a heterogeneous disorder with common clinical manifes- tations and, for the most part, common neuropatho- logic findings. The majority of cases of PD appear to be sporadic in nature (4); however, there may be genetic risk factors that increase the likelihood of developing PD, much in the same way that the apoE4 allele increases the risk of developing Alzheimer disease (AD) (5). Familial PD with specific genetic defects may account for fewer than 10% of all cases of PD (4); however, the identifica- tion of these rare genes and their functions has provid- ed tremendous insight into the pathogenesis of PD and opened up new areas of investigation (6, 7).