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.

Abnormal accumulation of misfolded tau aggregates is a pathological hallmark of various tauopathies including Alzheimer’s disease (AD). Although tau is a cytosolic microtubule-associated protein enriched in neurons, it is also found in extracellular milieu, such as interstitial fluid, cerebrospinal fluid, and blood. Accumulating evidence showed that pathological tau spreads along anatomically connected areas in the brain through intercellular transmission and templated misfolding, thereby inducing neurodegeneration and cognitive dysfunction. In line with this, the spatiotemporal spreading of tau pathology is closely correlated with cognitive decline in AD patients. Although the secretion and uptake of tau involve multiple different pathways depending on tau species and cell types, a growing body of evidence suggested that tau is largely secreted in a vesicle-free forms. In this regard, the interaction of vesicle-free tau with membrane is gaining growing attention due to its importance for both of tau secretion and uptake as well as aggregation. Here, we review the recent literature on the mechanisms of the tau-membrane interaction and highlights the roles of lipids and proteins at the membrane in the tau-membrane interaction as well as tau aggregation.

Chronic neuroinflammation is a common feature of the aged brain, and its association with the major neurodegenerative changes involved in cognitive impairment and motor dysfunction is well established. One of the most potent antiaging interventions tested so far is dietary restriction (DR), which extends the lifespan in various organisms. Microglia and astrocytes are two major types of glial cells involved in the regulation of neuroinflammation. Accumulating evidence suggests that the age-related proinflammatory activation of astrocytes and microglia is attenuated under DR. However, the molecular mechanisms underlying DR-mediated regulation of neuroinflammation are not well understood. Here, we review the current understanding of the effects of DR on neuroinflammation and suggest an underlying mechanistic link between DR and neuroinflammation that may provide novel insights into the role of DR in aging and age-associated brain disorders.