c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease

Lindholm, Dan; Pham, Dan Duc; Cascone, A; Eriksson, Ove; Wennerberg, Krister; Saarma, Märt

doi:10.3389/fnagi.2016.00254

Cited by 41 publications

(41 citation statements)

References 47 publications

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“…Studies indicate that c-Abl might be a promising therapeutic target for α-synucleinopathy [24,25,45,71] and a recent study demonstrated that a pharmacological c-Abl inhibitor, nilotinib (Nilo) enable to cross blood brain barrier [72,73]. The previous c-Abl inhibition study [25] showed that Nilo treatment of A53T transgenic mice starting at early ages (6-8 months old) lead to reduced levels of total αS levels in the forebrain regions but the effects of Nilo on overt αS pathology (pS129αS) and the disease onset was not reported.…”

Section: Pharmacological Inhibition Of C-abl Using Nilotinib Modulatementioning

confidence: 99%

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Karim

Liao

Kim

et al. 2020

Mol Neurodegeneration

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Background: Studies link c-Abl activation with the accumulation of pathogenic α-synuclein (αS) and neurodegeneration in Parkinson's disease (PD). Currently, c-Abl, a tyrosine kinase activated by cellular stress, is thought to promote αS pathology by either directly phosphorylating αS or by causing autophagy deficits. Methods: αS overexpressing transgenic (Tg) mice were used in this study. A53T Tg mice that express high levels of human mutant A53TαS under the control of prion protein promoter. Two different approaches were used in this study. Natural aging and seeding model of synucleinopathy. In seeding model, intracortical/intrastriatal (IC/IS) stereotaxic injection of toxic lysates was done using tissue lysates from end-stage symptomatic mice. In this study, nilotinib and pifithrin-α was used as a c-Abl and p53 inhibitor, respectively. Both Tg and non-transgenic (nTg) mice from each group were subjected to nilotinib (10 mg/kg) or vehicle (DMSO) treatment. Frozen brain tissues from PD and control human cases were analyzed. In vitro cells study was implied for c-Abl/p53 genetic manipulation to uncover signal transduction. Results: Herein, we show that the pathologic effects of c-Abl in PD also involve activation of p53, as c-Abl activation in a transgenic mouse model of α-synucleinopathy (TgA53T) and human PD cases are associated with the increased p53 activation. Significantly, active p53 in TgA53T neurons accumulates in the cytosol, which may lead to inhibition of autophagy. Thus, we hypothesized that c-Abl-dependent p53 activation contributes to autophagy impairment in α-synucleinopathy. In support of the hypothesis, we show that c-Abl activation is sufficient to inhibit autophagy in p53-dependent manner. Moreover, inhibition of either c-Abl, using nilotinib, or p53, using pifithrin-α, was sufficient to increase autophagic flux in neuronal cells by inducing phosphorylation of AMP-activated kinase (AMPK), ULK1 activation, and down-regulation of mTORC1 signaling. Finally, we show that pharmacological attenuation of c-Abl activity by nilotinib treatment in the TgA53T mouse model reduces activation of p53, stimulates autophagy, decreases accumulation αS pathology, and delays disease onset. Conclusion: Collectively, our data show that c-Abl activation by α-synucleinopathy causes p53 dependent autophagy deficits and both c-Abl and p53 represent therapeutic target for PD.

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Section: Pharmacological Inhibition Of C-abl Using Nilotinib Modulatementioning

confidence: 99%

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Karim

Liao

Kim

et al. 2020

Mol Neurodegeneration

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“…It acts as an inhibitor of c-abl, an oncogene involved in the regulation of cell growth, differentiation, proliferation and survival of cells. Increased levels of c-abl have been associated with PD, which is thought to result in an increase in phosphorylation and aggregation of α-synuclein ( Brahmachari et al, 2016 ; Lindholm et al, 2016 ). In addition, an increase in c-abl activity leads to a reduction in the function of parkin, which is a key protein in mitochondrial biogenesis, and in which mutations result in familial PD ( Lonskaya et al, 2014 ).…”

Section: α-Synuclein As a Therapeutic Targetmentioning

confidence: 99%

Emerging Treatment Approaches for Parkinson’s Disease

2018

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Parkinson’s disease (PD) is the second most common neurodegenerative disease, manifesting as a characteristic movement disorder with a number of additional non-motor features. The pathological hallmark of PD is the presence of intra-neuronal aggregates of α-synuclein (Lewy bodies). The movement disorder of PD occurs largely due to loss of dopaminergic neurons of the substantia nigra, resulting in striatal dopamine depletion. There are currently no proven disease modifying treatments for PD, with management options consisting mainly of dopaminergic drugs, and in a limited number of patients, deep brain stimulation. Long-term use of established dopaminergic therapies for PD results in significant adverse effects, and there is therefore a requirement to develop better means of restoring striatal dopamine, as well as treatments that are able to slow progression of the disease. A number of exciting treatments have yielded promising results in pre-clinical and early clinical trials, and it now seems likely that the landscape for the management of PD will change dramatically in the short to medium term future. Here, we discuss the promising regenerative cell-based and gene therapies, designed to treat the dopaminergic aspects of PD whilst limiting adverse effects, as well as novel approaches to reducing α-synuclein pathology.

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“…Trials of disease-modifying therapies in Parkinson’s are currently underway, with the ultimate aim of slowing the disease. Targets include the lysosomal pathway [ 119 ] and immunotherapies targeted against alpha synuclein [ 120 ] as well as repurposing of established drugs [ 3 ]. Whether these treatments will have specific effects on slowing cognitive involvement in PD or in PD-MCI will need to be tested.…”

Section: Current Challenges and Controversiesmentioning

confidence: 99%

Mild Cognitive Impairment in Parkinson’s Disease—What Is It?

Weil

Costantini²,

Schrag³

2018

Curr Neurol Neurosci Rep

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Purpose of ReviewMild cognitive impairment is a common feature of Parkinson’s disease, even at the earliest disease stages, but there is variation in the nature and severity of cognitive involvement and in the risk of conversion to Parkinson’s disease dementia. This review aims to summarise current understanding of mild cognitive impairment in Parkinson’s disease. We consider the presentation, rate of conversion to dementia, underlying pathophysiology and potential biomarkers of mild cognitive impairment in Parkinson’s disease. Finally, we discuss challenges and controversies of mild cognitive impairment in Parkinson’s disease.Recent FindingsLarge-scale longitudinal studies have shown that cognitive involvement is important and common in Parkinson’s disease and can present early in the disease course. Recent criteria for mild cognitive impairment in Parkinson’s provide the basis for further study of cognitive decline and for the progression of different cognitive phenotypes and risk of conversion to dementia.SummaryImproved understanding of the underlying pathology and progression of cognitive change are likely to lead to opportunities for early intervention for this important aspect of Parkinson’s disease.

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c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease

Cited by 41 publications

References 47 publications

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

α-Synucleinopathy associated c-Abl activation causes p53-dependent autophagy impairment

Emerging Treatment Approaches for Parkinson’s Disease

Mild Cognitive Impairment in Parkinson’s Disease—What Is It?

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