p21-activated kinase 4 controls the aggregation of α-synuclein by reducing the monomeric and aggregated forms of α-synuclein: involvement of the E3 ubiquitin ligase NEDD4-1 (original) (raw)
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The aggregation of alpha synuclein (a-syn) is a neuropatho-logical feature that defines a spectrum of disorders collectively termed synucleinopathies, and of these, Parkinson's disease (PD) is arguably the best characterized. Aggregated a-syn is the primary component of Lewy bodies, the defining pathological feature of PD, while mutations or multiplications in the a-syn gene result in familial PD. The high correlation between a-syn burden and PD has led to the hypothesis that a-syn aggregation produces toxicity through a gain-of-function mechanism. However, a-syn has been implicated to function in a diverse range of essential cellular processes such as the regulation of neurotransmission and response to cellular stress. As such, an alternative hypothesis with equal explanatory power is that the aggregation of a-syn results in toxicity because of a toxic loss of necessary a-syn function, following sequestration of functional forms a-syn into insoluble protein aggregates. Within this review, we will provide an overview of the literature linking a-syn to PD and the knowledge gained from current a-syn-based animal models of PD. We will then interpret these data from the viewpoint of the a-syn loss-of-function hypothesis and provide a potential mechanistic model by which loss of a-syn function could result in at least some of the neurodegeneration observed in PD. By providing an alternative perspective on the etiopathogenesis of PD and synucleinopathies, this may reveal alternative avenues of research in order to identify potential novel therapeutic targets for disease modifying strategies.
Viral vector-mediated overexpression of α-synuclein as a progressive model of Parkinson’s disease
Progress in Brain Research, 2010
The discovery of the role of a-synuclein in the pathogenesis of Parkinson's disease (PD) has opened new possibilities for the development of more authentic models of Parkinson's disease. Recombinant adeno-associated virus (AAV) and lentivirus (LV) vectors are efficient tools for expression of genes locally in subsets of neurons in the brain and can be used to express human wildtype or mutated a-synuclein selectively in midbrain dopamine neurons. Using this approach, it is possible to trigger extensive PD-like cellular and axonal pathologies in the nigrostriatal projection, involving abnormal protein aggregation, neuronal dysfunction, and cell death that develop progressively over time. Targeted overexpression of human a-synuclein in midbrain dopamine neurons, using AAV vectors, reproduces many of the characteristic features of the human disease and provides, for the first time, a model of progressive PD that can be applied to both rodents and primates.
Journal of Neurochemistry, 2007
There is increasing evidence that aggregation of a-synuclein contributes to the functional and structural deterioration in the CNS of Parkinson's disease patients and transgenic animal models. a-Synuclein binds to various cellular proteins and aggregated a-synuclein species may affect their physiological function. In the present study, we used protein arrays spotted with 178 active human kinases for a large-scale analysis of the effects of recombinant a-synuclein on kinase activities. Incubation with globular a-synuclein oligomers significantly inhibited autophosphorylation of p21-activated kinase (PAK4) compared to treatment with monomeric a-synuclein or b-synuclein. A concentration-dependent inhibition was also observed in a solution-based kinase assay. To show in vivo relevance, we analyzed brainstem protein extracts from a-synuclein (A30P) transgenic mice where accumulation of a-synuclein oligomers has been demonstrated. By immunoblotting using a phospho-specific antibody, we detected a significant decline in phosphorylation of LIM kinase 1, a physiological substrate for PAK4. Suppression of PAK activity by amyloid-b oligomers has been reported in Alzheimer's disease. Thus, PAKs may represent a target for various neurotoxic protein oligomers, and signaling deficits may contribute to the behavioral defects in chronic neurodegenerative diseases.
Neuron, 2009
Mutations in α-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T αsynuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of α-synuclein in A53T mice, likely resulted from the impairment of microtubule dynamics, Golgi organization, and ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure, suppressed the aggregation and somatic accumulation of α-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that over-expression of LRRK2 enhances α-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating α-synuclein-induced neurodegeneration.
Journal of Biological Chemistry, 2005
Aggregation of the nerve cell protein ␣-synuclein is a characteristic of the common neurodegenerative ␣-synucleinopathies like Parkinson's disease and Lewy body dementia, and it plays a direct pathogenic role as demonstrated by early onset diseases caused by missense mutations and multiplication of the ␣-synuclein gene. We investigated the existence of ␣-synuclein proaggregatory brain proteins whose dysregulation may contribute to disease progression, and we identified the brain-specific p25␣ as a candidate that preferentially binds to ␣-synuclein in its aggregated state. Functionally, purified recombinant human p25␣ strongly stimulates the aggregation of ␣-synuclein in vitro as demonstrated by thioflavin-T fluorescence and quantitative electron microscopy. p25␣ is normally only expressed in oligodendrocytes in contrast to ␣-synuclein, which is normally only expressed in neurons. This expression pattern is changed in ␣-synucleinopathies. In multiple systems atrophy, degenerating oligodendrocytes displayed accumulation of p25␣ and dystopically expressed ␣-synuclein in the glial cytoplasmic inclusions. In Parkinson's disease and Lewy body dementia, p25␣ was detectable in the neuronal Lewy body inclusions along with ␣-synuclein. The localization in ␣-synuclein-containing inclusions was verified biochemically by immunological detection in Lewy body inclusions purified from Lewy body dementia tissue and glial cytoplasmic inclusions purified from tissue from multiple systems atrophy. We suggest that p25␣ plays a pro-aggregatory role in the common neurodegenerative disorders hallmarked by ␣-synuclein aggregates. The group of ␣-synucleinopathies is dominated by the frequent neurodegenerative disorders Parkinson's disease (PD), 1
Acta Neuropathologica Communications, 2021
Recent studies suggest that brain cell type specific intracellular environments may play important roles in the generation of structurally different protein aggregates that define neurodegenerative diseases. Using human induced pluripotent stem cells (hiPSC) and biochemical and vibrational spectroscopy techniques, we studied whether Parkinson’s disease (PD) patient genomes could modulate alpha-synuclein (aSYN) protein aggregates formation. We found increased β-sheets and aggregated aSYN in PD patient hiPSC-derived midbrain cells, compared to controls. Importantly, we discovered that aSYN protein aggregation is modulated by patient brain cells’ intracellular milieus at the primary nucleation phase. Additionally, we found changes in the formation of aSYN fibrils when employing cellular extracts from familial PD compared to idiopathic PD, in a Thioflavin T-based fluorescence assay. The data suggest that changes in cellular milieu induced by patient genomes trigger structural changes of...
Parkinsona’s disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, in...
Journal of Neuroscience, 2012
Several lines of evidence suggest that phosphorylation of ␣-synuclein (␣-syn) at S87 or S129 may play an important role in regulating its aggregation, fibrillogenesis, Lewy body formation, and neurotoxicity in vivo. However, whether phosphorylation at these residues enhances or protects against ␣-syn toxicity in vivo remains unknown. In this study, we investigated the cellular and behavioral effect of overexpression of wild-type (WT), S87A, and S87E ␣-syn to block or to mimic S87 phosphorylation, respectively, in the substantia nigra of Wistar rats using recombinant adeno-associated vectors. Our results revealed that WT and S87A overexpression induced ␣-syn aggregation, loss of dopaminergic neurons, and fiber pathology. These neuropathological effects correlated well with the induction of hemi-parkinsonian motor symptoms. Strikingly, overexpression of the phosphomimic mutant S87E did not show any toxic effect on dopaminergic neurons and resulted in significantly less ␣-syn aggregates, dystrophic fibers, and motor impairment. Together, our data demonstrate, for the first time, that mimicking phosphorylation at S87 inhibits ␣-syn aggregation and protects against ␣-syn-induced toxicity in vivo, suggesting that phosphorylation at this residue would play an important role in controlling ␣-syn neuropathology. In addition, our results provide strong evidence for a direct correlation between ␣-syn-induced neurotoxicity, fiber pathology, and motor impairment and the extent of ␣-syn aggregation in vivo, suggesting that lowering ␣-syn levels and/or blocking its aggregation are viable therapeutic strategies for the treatment of Parkinson's disease and related synucleinopathies.
FEBS Journal, 2010
Parkinson's disease (PD) is a sporadic neurodegenerative disorder of unknown etiology characterized mainly by the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and depletion of striatal dopamine. Dopaminergic neuronal death is accompanied by the appearance of Lewy bodies (LB), intracytoplasmic inclusions immunoreactive for a-synuclein, ubiquitin, 3-nitrotyrosine and neurofilament . Many of the genetic factors variously associated with PD, such as a-synuclein mutations and Abbreviations a-syn, human a-synuclein overexpressing cells; b-gal, b-galactosidase expressing cells; C1qBP, C1Q binding protein; CRMP4, collapsin response mediator protein 4; 2-DE, 2D electrophoresis; eIF5A, eukaryotic initiation factor 5A; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GO, Gene Ontology; GSK-3b, glycogen synthase kinase 3b; GSTp, glutathione S-transferase p; LB, Lewy bodies; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NF-jB, nuclear factor kappa B; PD, Parkinson's disease; Ran1BP, Ran 1 binding protein; RPLP2, 60S acidic ribosomal protein P2; SNpc, substantia nigra pars compacta; VDAC-2, voltage-dependent anion channel 2.