Genetics of parkin-linked disease

Abstract

Research into Parkinson's disease (PD), once considered the archetypical non-genetic neurodegenerative disorder, has been revolutionized by the identification of a number of genes, mutations of which underlie various familial forms of the disease. Whereas such mutations appear to exist in a relatively small number of individuals from a few families, the study of the function of these genes promises to reveal the fundamental disease pathogenesis, not only of familial forms of the disease, but also of the much more common sporadic PD. The observation that mutations in the second identified PD locus (parkin) are common in juvenile- and early-onset PD and increasing evidence supporting a direct role for parkin in late-onset disease make this gene a particularly compelling candidate for intensified investigation. The determination of the frequency and effect of parkin mutations in various subsets of PD will be crucial for understanding the way in which parkin is related to neurodegenerative mechanisms, and whether these subsets might be effectively identified and treated. In addition, many aspects of parkin-linked disease, originally thought to be well defined, have now been obscured both by genetic studies that preclude a simple model of disease transmission and by clinical and pathological studies that demonstrate broad variability in cases with parkin mutations. Future studies that address the issues in question should have a far-reaching impact in downstream biochemical studies and our understanding of parkin's role in PD.

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

“…To date, hundreds of cases with a wide variety of Parkin mutations, from large exon rearrangements to single base pair deletions and insertions, have been reported. Mutations have been found in nearly every ethnicity studied [222]. Although they are more frequent among early-onset and familial cases, they have also been detected among late-onset cases [223].…”

“…Parkin mutations account for about half of cases with autosomal recessive early onset (<50 years) PD, 10-20% of non-familial PD cases with early onset and 0.4-0.7% of all non-familial PD in the general population [222,224]. Many mutations are homozygous or compound heterozygous, but there also exist cases with one single Parkin mutation [222,225], although it is controversial whether these are disease-causing mutations or merely polymorphisms [226].…”

“…Many mutations are homozygous or compound heterozygous, but there also exist cases with one single Parkin mutation [222,225], although it is controversial whether these are disease-causing mutations or merely polymorphisms [226].…”

Increased glutathione S -transferase activity rescues dopaminergic neuron loss in a Drosophila model of Parkinson's disease

“…Loss-of-function mutations of parkin are a common cause of autosomal recessive juvenile parkinsonism (ARJP), and parkin dysfunction may also contribute to late-onset sporadic PD (2)(3)(4)(5)(6). Patients with parkin mutations display many of the typical features of idiopathic PD, including locomotor dysfunction, reduced mitochondrial complex I activity, and degeneration of DA neurons in the substantia nigra.…”

Zinc supplement greatly improves the condition of parkin mutant Drosophila

“…Oxidative stress is considered to be a major factor in the pathogenesis of PD, as evidenced by an elevated content of redox-active iron and lipid peroxides in the diseased brain, impaired mitochondrial function, and alterations in the antioxidant defense mechanisms (Dexter et al, 1989;Jenner and Olanow, 1996;Greene et al, 2003;Pesah et al, 2004). Mutations in six genes, including parkin which encodes an E3 ubiquitin ligase, have been associated with rare, early-onset, familial forms of PD (West and Maidment, 2004;Gasser, 2005;Sang et al, 2007). Interestingly, some alleles of these genes might be susceptibility factors for environmental toxins (Choi et al, 2000;Warner and Schapira, 2003;Bueler, 2009).…”