The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease
ABSTRACT Mutations in the PINK1 gene cause autosomal recessive parkinsonism characterized by early onset and a variable phenotypic presentation. A patient homozygous for the Ala168Pro mutation has been fully characterized clinically. Apart from onset at age 39 years and the excellent and sustained response to levodopa, all clinical and laboratory features, including SPECT and assessment of autonomic function, were indistinguishable from typical idiopathic Parkinson disease.
Full-textDOI: · Available from: Luigi Romito, Apr 08, 2014
- SourceAvailable from: Rafael Castro Fuentes
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- "The UCH-L1 mutation impairs the ubiquitin-proteasome system (Osaka et al., 2003; Li et al., 2004), promoting both PD (Leroy et al., 1998) and aging (Marzban et al., 2002). PINK1 facilitates axonal transport and degradation of damaged mitochondrias (Valente et al., 2004a; Liu, 2014), and this PINK1 activity is altered in both the PD (Valente et al., 2004b; Albanese et al., 2005; Gelmetti et al., 2008) and aging (Wood-Kaczmar et al., 2008; Vincow et al., 2013) brain. The DJ-1 protein protects cells against oxidative stressors (Moore et al., 2005). "
ABSTRACT: Available data show marked similarities for the degeneration of dopamine cells in Parkinson's disease (PD) and aging. The etio-pathogenic agents involved are very similar in both cases, and include free radicals, different mitochondrial disturbances, alterations of the mitophagy and the ubiquitin-proteasome system. Proteins involved in PD such as α-synuclein, UCH-L1, PINK1 or DJ-1, are also involved in aging. The anomalous behavior of astrocytes, microglia and stem cells of the subventricular zone (SVZ) also changes similarly in aging brains and PD. Present data suggest that PD could be the expression of aging on a cell population with high vulnerability to aging. The future knowledge of mechanisms involved in aging could be critical for both understanding the etiology of PD and developing etiologic treatments to prevent the onset of this neurodegenerative illness and to control its progression.Frontiers in Neuroanatomy 08/2014; 8:80. DOI:10.3389/fnana.2014.00080 · 4.18 Impact Factor
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- "Most remarkably, all these very distinct mutations can generate rather indistinguishable PD pathology respecting brain region specific neuron loss. Moreover, several oxidative stress inducers such as MPTP (1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridin), 6-hydroxydopamine (6-OHDA) or paraquat, can faithfully reproduce comparable neuronal death pattern similar to that observed in PD [7-9]. This indicates that some intrinsic brain structural dynamics set the tune in PD progression. "
ABSTRACT: ABSTRACT: Parkinson's disease (PD) is histologically well defined by its characteristic degeneration of dopaminergic neurons in the substantia nigra pars compacta. Remarkably, divergent PD-related mutations can generate comparable brain region specific pathologies. This indicates that some intrinsic region-specificity respecting differential neuron vulnerability exists, which codetermines the disease progression. To gain insight into the pathomechanism of PD, we investigated protein expression and protein oxidation patterns of three different brain regions in a PD mouse model, the PINK1 knockout mice (PINK1-KO), in comparison to wild type control mice. The dysfunction of PINK1 presumably affects mitochondrial turnover by disturbing mitochondrial autophagic pathways. The three brain regions investigated are the midbrain, which is the location of substantia nigra; striatum, the major efferent region of substantia nigra; and cerebral cortex, which is more distal to PD pathology. In all three regions, mitochondrial proteins responsible for energy metabolism and membrane potential were significantly altered in the PINK1-KO mice, but with very different region specific accents in terms of up/down-regulations. This suggests that disturbed mitophagy presumably induced by PINK1 knockout has heterogeneous impacts on different brain regions. Specifically, the midbrain tissue seems to be most severely hit by defective mitochondrial turnover, whereas cortex and striatum could compensate for mitophagy nonfunction by feedback stimulation of other catabolic programs. In addition, cerebral cortex tissues showed the mildest level of protein oxidation in both PINK1-KO and wild type mice, indicating either a better oxidative protection or less reactive oxygen species (ROS) pressure in this brain region. Ultra-structural histological examination in normal mouse brain revealed higher incidences of mitophagy vacuoles in cerebral cortex than in striatum and substantia nigra. Taken together, the delicate balance between oxidative protection and mitophagy capacity in different brain regions could contribute to brain region-specific pathological patterns in PD.Proteome Science 09/2011; 9(1):59. DOI:10.1186/1477-5956-9-59 · 1.88 Impact Factor
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- "Also common were levodopa-induced dyskinesias, resting tremor, and asymmetry at onset, postural instability (63%), on/off phenomenon (60%), and gait impairment (55%). As in parkin disease, except of the earlier average age of onset, no single feature can separate PINK1-disease from idiopathic PD . There are some indications that PINK1-mutated patients have a higher prevalence of psychiatric disturbances, particularly anxiety and depression, which is only relatively rarely observed in parkin cases . "
ABSTRACT: Over the last few years, genetic findings have changed our views on Parkinson's disease (PD), as mutations in a growing number of genes are found to cause monogenic forms of the disorder. Point mutations in the gene for α-synuclein, as well as duplications and triplications of the wild-type gene cause a dominant form of PD in rare families, pointing towards mishandling of this protein as a crucial step in the molecular pathogenesis of the disorder. Mutations in the gene for leucine-rich repeat kinase 2 (LRRK2) have recently been identified as a much more common cause for dominant PD, while mutations in the parkin gene, in DJ-1, PINK1 and ATP13A2 all cause autosomal-recessive parkinsonism of early onset. Mutations in recessive genes probably are pathogenic through loss-of-function mechanisms, suggesting that their wild-type products protect dopaminergic cells against a variety of insults. Evidence is emerging that at least some of these genes may play a direct role in the etiology of the common sporadic form of PD. Further, it is likely that the cellular pathways identified in rare monogenic variants of the disease also shed light on the molecular pathogenesis in typical sporadic PD.Biochimica et Biophysica Acta 07/2009; 1792(7-1792):587-596. DOI:10.1016/j.bbadis.2008.12.007 · 4.66 Impact Factor