Elsevier

Neurologic Clinics

Volume 27, Issue 3, August 2009, Pages 583-603
Neurologic Clinics

Etiology and Pathogenesis of Parkinson Disease

https://doi.org/10.1016/j.ncl.2009.04.004Get rights and content

Section snippets

Genetic factors

Several recent case control studies have confirmed that PD is more common in relatives of PD cases compared with matched controls.10, 11, 12, 13 Overall, the relative risk in first-degree relatives of PD cases has increased approximately 2 to 3-fold.14 A large PD twin study showed no significant concordance for PD among monozygotic twins, suggesting no significant genetic contribution to PD.15 However, for those with onset before age 50 years, the concordance rate was significant, implying that

Environmental factors

The traditional view has been that the environment must play a significant role in the etiology of PD. This has been supported over the years with the description of cases of parkinsonism in response to certain dopaminergic nigral toxins such as MPTP. The role of the environment was reenforced by the failure of twin studies to unequivocally demonstrate significant concordance, particularly in late-onset cases. However, the discovery of single gene mutations as causes of familial PD has led to a

Pathogenesis of Parkinson disease

Even before the discovery of the first gene mutation for PD, biochemical analyses of postmortem brains had established mitochondrial dysfunction and oxidative stress as major participants in the pathogenesis of PD. Their role has only been reinforced by the discovery of several genetic causes for PD and an understanding of their mechanism of action.

Defects of the mitochondrial respiratory chain and, in particular, complex I deficiency were traditionally associated with mitochondrial myopathies.

Autophagy

Intracellular protein degradation is achieved through a combination of the UPS and autophagic pathways. However, the role of the UPS in alpha-synuclein metabolism remains unclear. Attention has recently focused on the potential contribution of autophagy to the pathogenesis of neurodegenerative diseases.173, 174, 175 Autophagy comprises 3 separate pathways: macroautophagy (MA), microautophagy, and chaperone-mediated autophagy (CMA). MA involves the formation of double-membraned autophagosomes,

Summary

The last few years have witnessed important advances in our understanding of the etiology and pathogenesis of PD. Several features have become self-evident. The first is that there are multiple causes of the clinical phenotype that we currently recognize as PD, and these same causes can result in a spectrum of phenotypes. Thus, there is some disconnect between genotype and phenotype. Secondly, there is variation in the pathology that may be induced by the specific gene mutations, a further

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