PARKIN/PINK1 Pathway for the Selective Isolation and Degradation of Impaired Mitochondria
Mutations in PARK2 and PARK6 are the most common genetic cause of early onset parkinsonism. Since their gene products, PARKIN and PINK1, were shown to function in a common pathway critical for mitochondrial integrity in 2006, research into PARKIN/PINK1 mi
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PARKIN/PINK1 Pathway for the Selective Isolation and Degradation of Impaired Mitochondria Derek P. Narendra
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Clinical Features of Parkinsonism Due to PARKIN and PINK1 Mutations, the Human Phenotype
Parkinson’s disease (PD) is a progressive movement disorder affecting 1 % of the population over 60 years of age [1]. It is characterized clinically by slowness of movement (bradykinesia), tremor at rest, rigidity, and postural instability. These signs are due to loss of the substantia nigra neurons supplying dopamine to the basal ganglia, which are critical for motor control. Early in the disease course, treatment with the metabolic precursor to dopamine, L-DOPA, relieves many of these motor symptoms and reduces mortality from PD complications [2]. However, the disease remains disabling in its advanced stages with excess mortality compared to the general population [3]. A principal motivation for studying genetic forms of PD is the hope that novel targets will be uncovered to slow or halt disease progression. Mutations in the gene PARK2 (hereafter PARKIN) coding for the PARKIN protein and mutations in PARK6 (hereafter PINK1) coding for the PINK1 protein are the most common genetic causes of parkinsonism with onset before the age of 45 [4, 5]. A recent systematic review estimates that PARKIN mutations are responsible for 8.6 % of early onset PD cases (and about 0.3 % of PD cases overall), whereas PINK1 mutations account for 3.7 % of early onset cases [6]. PARKIN and PINK1 mutations have a recessive pattern of inheritance. Additionally, causative mutations have been identified in virtually every domain of PARKIN and PINK1, consistent with the proposed loss of function mechanism of disease pathogenesis. Clinically, the parkinsonian motor symptoms due to PARKIN and PINK1 mutations resemble early onset sporadic PD. Other neurologic systems spared in sporadic PD
D.P. Narendra, M.D., Ph.D. (*) Intramural Program, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, 9600 Rockville Pike, 35A/GF149, Bethesda, MD 20892, USA e-mail: [email protected] © Springer International Publishing Switzerland 2016 L.M. Buhlman (ed.), Mitochondrial Mechanisms of Degeneration and Repair in Parkinson’s Disease, DOI 10.1007/978-3-319-42139-1_8
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are also spared in PARKIN and PINK1-related parkinsonism, and, in this sense, PARKIN and PINK1 mutations cause a relatively pure parkinsonian phenotype. This is in contrast to other causes of recessive parkinsonism such as mutations in ATP1A3, in which early dementia and pyramidal signs are often pronounced [7]. Although motor symptoms are characteristic, non-motor symptoms that are common in sporadic PD may be less common in parkinsonism due to PARKIN or PINK1 mutations. Unlike most patients with sporadic PD, for instance, patients with PARKIN and PINK1 mutations probably have a normal sense of smell [8]. Additionally, a recent report found that unlike most patients with sporadic PD, patients with PARKIN-related parkinsonism do not ex
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