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

Abstract

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.

Intranigral Administration of β-Sitosterol-β-D-Glucoside Elicits Neurotoxic A1 Astrocyte Reactivity and Chronic Neuroinflammation in the Rat Substantia Nigra

“…These results agree with a recent report showing that DMSO does not trigger apoptosis or senescence in the substantia nigra cells, neither elicits changes in the cytoskeleton or density of dendritic spines [38] or behavioral alterations [37]. Other authors that used 100% DMSO also do not report damage or altered function in vivo [77][78][79][80]. In contrast, other studies have reported that DMSO is toxic in cell cultures.…”

Adiponectin-mimetic novel nonapeptide rescues aberrant neuronal metabolic-associated memory deficits in Alzheimer’s disease

“…AMPK exerts a neuroprotective effect against various neurodegenerative injury, and reduced AMPK expression leads to neurodegeneration. In contrast, AMPK activation regulates neurodegeneration [ 35 , 36 , 52 – 54 ]. Activated AMPK regulates aberrant brain metabolism and reduces insulin resistance [ 14 – 16 , 55 , 56 ].…”

The effect of copy number on α-synuclein’s toxicity and its protective role in Bax-induced apoptosis, in yeast

“…Parkinson's disease (PD) is a severe neurodegenerative disorder which is categorised by bradykinesia (slow movement), postural instability, muscular rigidity and resting tremors [1,2]. Many PD cases are from an obscure cause, though some are known to be caused by missense mutations in the α-synuclein gene [3,4].…”

“…Rescue of Bax induced block of cell growth by untagged α-synuclein (1-3 copies) on GAL1p and α-synuclein-HA (1-3 copies) on MET25p(A) Growth on solid agar minimal medium plates of yeast transformants bearing one(1), two(2) or three (3) copies of the α-synuclein gene under the control of MET25 promoter (MET-α-syn-HA) and Bax gene under the control of GAL1 promoter (Bax). (B) Growth of yeast strains containing 1, 2 and 3 copies of α-synuclein-HA (MET25p) with a copy of Bax in a minimal liquid medium (SG + 0.1% glucose) along with controls.…”