Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease

Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Parkinsonism & Related Disorders (Impact Factor: 3.97). 10/2009; 15(10):721-7. DOI: 10.1016/j.parkreldis.2009.09.010
Source: PubMed


Recent authors have concluded that Parkinson's disease (PD) is too heterogeneous to still be considered a single discrete disorder. They advise broadening the concept of PD to include genetic parkinsonisms, and discard Lewy pathology as the confirmatory biomarker. However, PD seen in the clinic is more homogeneous than often recognized if viewed from a long-term perspective. With appropriate diagnostic criteria, it is consistently associated with Lewy neuropathology, which should remain the gold standard for PD diagnostic confirmation. PD seen in the clinic has an inexorable course with eventual development of not only levodopa-refractory motor symptoms, but often cognitive dysfunction and prominent dysautonomia. This contrasts with homozygous parkin, PINK1 or DJ1 parkinsonism, characterized by young-onset (usually <40 years), and a comparatively benign course of predominantly levodopa-responsive symptoms without dementia or prominent dysautonomia. Parkin neuropathology is non-Lewy, with neurodegeneration predominantly confined to substantia nigra (and locus ceruleus), consistent with the limited clinical phenotype. Given the restricted and persistently levodopa-responsive phenotype, these familial cases might be considered "nigropathies". Based on emerging laboratory evidence linking parkin and PINK1 (and perhaps DJ1) to mitochondrial dysfunction, these nigropathies may represent nigral mitochondrial cytopathies. The dopaminergic substantia nigra is uniquely vulnerable to mitochondrial challenges, which might at least be partially attributable to large energy demands consequent to thin, unmyelinated axons with enormous terminal fields. Although sporadic PD is also associated with mitochondrial dysfunction, Lewy neurodegeneration represents a more pervasive disorder with perhaps a second, or different primary mechanism.

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    • "DJ-1 also stabilizes the anti-oxidant transcriptional master regulator Nrf2 (located in the nucleus of SN neurons) by preventing association with its inhibitor protein KEap1. In the same pathway, modification of cysteine sulfinic acid might enhance its association with mitochondria, while oxidative stress promotes the interaction of mutated cysteine residues with parkin, linking DJ-1 and parkin (Ahlskog, 2009; Taira et al., 2004). LRRK2 resides throughout the cytosol but also associates with the OMM; its domains include a leucinerich repeat domain and a GTPase domain. "
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    ABSTRACT: The hallmark of dementia with Lewy bodies (DLB) is the “Lewy body”, an abnormal aggregation of alpha- synuclein found in some areas of the brain. The brain is the organ/system that is most vulnerable to this oxidative damage, and reactive oxygen species can cause neurodegenerative diseases. Different models of mitochondrial deregulation have been compared in DLB. The results are consistent with the hypothesis that alpha-synuclein affects the mitochondria them- selves, increasing their sensitivity or leading to cell death through protective (neurosin) and accelerating (cytochrome c) factors. This systematic review suggests that mitochondria play an important role in neurodegeneration and a crucial role in the formation of Lewy bodies. DLB is a disease characterized by abnormal accumulation of alpha-synuclein that could result in the release of cytochrome c and subsequent activation of the apop- totic cascade.
    Functional neurology 09/2015; 30(3):1-8. · 1.86 Impact Factor
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    • "Some of these Mendelian parkinsonism, such as those caused by dominant mutations in the alpha-synuclein (PARK1) or leucine-rich repeat kinase 2 (PARK8) gene, are more similar to the common, idiopathic PD form [5]. In other forms, such as those caused by recessive mutations in the parkin (PARK2), PINK1 (PARK6), DJ-1 (PARK7), and ATP13A2 (PARK9), the phenotype is more often atypical due to younger-onset, presence of additional clinical signs (dementia, pyramidal signs), or absence of Lewy body-pathology [6], [7], [8]. However, despite these atypical phenotypes, understanding the mechanisms of the Mendelian parkinsonisms might provide important clues into the pathways leading to the degeneration of the dopaminergic neurons, which might also be involved in the common forms of PD. "
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    ABSTRACT: Mutations in the F-box only protein 7 gene (FBXO7) cause PARK15, an autosomal recessive neurodegenerative disease presenting with severe levodopa-responsive parkinsonism and pyramidal disturbances. Understanding the PARK15 pathogenesis might thus provide clues on the mechanisms of maintenance of brain dopaminergic neurons, the same which are lost in Parkinson's disease. The protein(s) encoded by FBXO7 remain very poorly characterized. Here, we show that two protein isoforms are expressed from the FBXO7 gene in normal human cells. The isoform 1 is more abundant, particularly in primary skin fibroblasts. Both isoforms are undetectable in cell lines from the PARK15 patient of an Italian family; the isoform 1 is undetectable and the isoform 2 is severely decreased in the patients from a Dutch PARK15 family. In human cell lines and mouse primary neurons, the endogenous or over-expressed, wild type FBXO7 isoform 1 displays mostly a diffuse nuclear localization. An intact N-terminus is needed for the nuclear FBXO7 localization, as N-terminal modification by PARK15-linked missense mutation, or N-terminus tag leads to cytoplasmic mislocalization. Furthermore, the N-terminus of wild type FBXO7 (but not of mutant FBXO7) is able to confer nuclear localization to profilin (a cytoplasmic protein). Our data also suggest that overexpressed mutant FBXO7 proteins (T22M, R378G and R498X) have decreased stability compared to their wild type counterpart. In human brain, FBXO7 immunoreactivity was highest in the nuclei of neurons throughout the cerebral cortex, intermediate in the globus pallidum and the substantia nigra, and lowest in the hippocampus and cerebellum. In conclusion, the common cellular abnormality found in the PARK15 patients from the Dutch and Italian families is the depletion of the FBXO7 isoform 1, which normally localizes in the cell nucleus. The activity of FBXO7 in the nucleus appears therefore crucial for the maintenance of brain neurons and the pathogenesis of PARK15.
    PLoS ONE 02/2011; 6(2):e16983. DOI:10.1371/journal.pone.0016983 · 3.23 Impact Factor

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