Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies

Abstract

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.

The eIF2α kinase HRI triggers the autophagic clearance of cytosolic protein aggregates

“…It is thus plausible that HSPB8, possibly together with a selection of other HSPs, would play a role in the general control of HRI-dependent proteostasis through autophagy. This may have implications for neurodegenerative disorders since autophagy, and more specifically BAG3and HSPB8-dependent chaperone-assisted selective autophagy, has been shown to play important homeostatic functions in the brain 36 .…”

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation

“…In the brain, phytochemicals produce several biological effects such as modulation of neurotransmitter metabolism and release, growth factor induction, antioxidant, and anti-inflammatory activity, as well as regulation of mitochondrial homeostasis, and maintenance of proteostasis, which is bound, at least in part, to targeting alterations of cell-clearing systems [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. When considered individually, none of the effects produced by phytochemicals is expected to fully achieve neuro-health benefits and/or therapeutic efficacy, since different etiological factors may combine to produce a chain of intermingled pathological events in neurodegeneration [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. Far from being independent, the multi-target effects of phytochemicals are interconnected and implicated in most neurodegenerative disorders.…”

“…Far from being independent, the multi-target effects of phytochemicals are interconnected and implicated in most neurodegenerative disorders. These include alterations of glucose metabolism and redox imbalances occurring in the cellular environment, which may contribute to promoting mitochondrial damage and protein misfolding, meanwhile affecting protein quality control [ 10 , 13 , 14 ]. In fact, oxidative compounds and sugar residues may alter secondary protein structure and conformation, thus fostering protein misfolding and aggregation, which is exacerbated when the cell-clearing systems autophagy and proteasome are impaired [ 10 , 15 ].…”

“…These include alterations of glucose metabolism and redox imbalances occurring in the cellular environment, which may contribute to promoting mitochondrial damage and protein misfolding, meanwhile affecting protein quality control [ 10 , 13 , 14 ]. In fact, oxidative compounds and sugar residues may alter secondary protein structure and conformation, thus fostering protein misfolding and aggregation, which is exacerbated when the cell-clearing systems autophagy and proteasome are impaired [ 10 , 15 ]. Oxidative stress, coupled with the impaired removal of altered mitochondria by autophagy, which is named mitophagy, also contributes to the accumulation of damaged mitochondria which, in turn, fuels the release of reactive oxygen species (ROS) and pro-apoptotic caspases [ 16 , 17 ].…”

“…In this frame, an interdependency exists between oxidative/inflammatory events, mitochondrial damage, protein aggregation, and alterations of autophagy and proteasome, which are promiscuously implicated in various neurodegenerative proteinopathies [ 7 , 10 , 14 , 17 , 18 , 19 , 20 , 21 ]. It is now widely accepted that autophagy and proteasome are altered in both patients and experimental models of neurodegeneration, and their inhibition in experimental models reproduces key pathological features of neurodegeneration [ 7 , 10 , 21 , 22 , 23 , 24 ].…”