Genetics of Parkinsonism: a review

Abstract

Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1)

“…Recent molecular studies have uncovered several genes whose mutations produce familial PD transmitted as disorders with Mendelian inheritance [34][35][36] and several polymorphisms that are associated to a increased risk for sporadic PD. 37 There are no, however, studies related to the genetic mechanisms that control for the diversity of the clinical symptoms present in this disease.…”

A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

“…The gene for one rare autosomal recessive form of PD, which maps to chromosome 1p35-p36, has been cloned and found to code for the PINK1 (PTEN-induced kinase) protein, a kinase localized in the mitochondrion (221). A more common autosomal recessive locus, the parkin gene on chromosome 6q25.2-27, is a E3 ubiquitin ligase (228). Genetic inactivation of parkin in the mouse resulted in nigrostriatal defects associated with a decreased abundance of several mitochondrial proteins including the E1α subunit of pyruvate dehydrogenase, the 24-and 30-kDa subunits of complex I and the Vb subunit of complex IV and a general decrease in mitochondrial state III respiration.…”

Regulation of p53 by Activated Protein Kinase C-δ during Nitric Oxide-induced Dopaminergic Cell Death

“…Although the etiological causes of PD have not been fully elucidated, studies have identified major risk factors that include aging, exposure to environmental hazards, and genetic predisposition (1)(2)(3)(4)(5)(6). Under these pathological conditions, the expression of inducible NO synthase may be induced in glia (especially astrocytes and microglia) by inflammatory mediators (7).…”