Age-related neurodegeneration is characterized by the aggregation of a small number of proteins, including α-synuclein, that can become altered in a manner that encourages other molecules of the same protein to alter in the same way. These altered forms of protein precipitate to form structures solid fibrils and deposits, surrounded by a halo of toxic biochemistry that impairs cell function. Today’s open access paper explores just one of the ways in which α-synuclein harms cells, in this case by downregulating the operation of autophagy.
Autophagy is the name given to a collection of cellular maintenance processes that are particularly important in long-lived cells such as the neurons of the central nervous system. Autophagy recycles damaged and unwanted structures and proteins in the cell. When it falters, cells accumulate dysfunctional components and suffer accordingly. Unfortunately, evidence suggests that the efficiency of autophagy declines with age, though the underlying causes of this issue are poorly understood. Increases in autophagy are thought to be responsible for the extension of life produced by the practice of calorie restriction, as well as many other interventions shown to improve health and extend health in
Parkinson’s disease (PD) is a common late onset progressive neurodegenerative disease most characterized by movement disorder resulting from the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In addition, PD is also characterized by the presence of protein inclusions known as Lewy bodies (LB) and Lewy neurites (LN), which are composed of aggregated α-synuclein (αS), in multiple neuronal populations. While the etiology of PD is unknown in most cases, αS abnormalities are mechanistically linked to PD pathogenesis as mutations in αS cause PD in a small number of familial PD pedigrees. Currently, how αS abnormalities cause neuronal dysfunction and degeneration is not fully understood. However, studies have implicated oxidative stress in the pathogenesis of PD and dysfunction in proteostasis. While oxidative stress in neurons has complex and multifaceted effects, recent reports suggest that activation of c-Abl, a non-receptor tyrosine kinase, can be stimulated by oxidative stress. And thus, may be linked to the pathogenesis of PD, Alzheimer’s disease (AD) and other neurodegenerative diseases.
c-Abl is a tyrosine kinase known to be activated by cellular stressors, such as oxidative stress and DNA damage. c-Abl also functions to regulate many fundamental cellular processes, such as cell survival, migration, and growth factor signaling. Emerging studies implicate aberrant c-Abl activity in neurodegenerative disease. In PD, c-Abl is activated in regions showing DAergic neurodegeneration, such as the striatum and SNpc, and inactivates parkin by phosphorylation. Significantly, c-Abl activation is linked to αS pathology as increased αS expression in cells and transgenic (Tg) mice was associated with c-Abl activation, and inhibition of c-Abl or the loss of c-Abl expression leads to attenuation of αS levels and/or aggregation. Some of these studies implicate c-Abl as an inhibitor of autophagy. However, it is unknown how c-Abl regulates autophagy.
We show that c-Abl-dependent inhibition of autophagy is p53 dependent, 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. Further, both c-Abl and p53 activity is positively associated with mTOR activity and inversely associated with AMPK/ULK1 activity, showing that c-Abl and p53 directly impact the pathways relevant to autophagy regulation. Finally, we show that c-Abl-dependent pathway is a significant target for therapeutic intervention as pharmacological inhibition of c-Abl delays disease onset in two independent Tg mouse models of α-synucleinopathy. Our data identify a novel pathway for regulation of autophagy in α-synucleinopathy and support the development of c-Abl and p53 inhibitors for disease modifying therapies for PD and other α-synucleinopathies.