Protein phosphorylation in neurodegeneration: friend or foe?

Abstract

Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system.

Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

“…Of note, this is opposite of the current paradigm for tau aggregation, which is believed to be potentiated by hyper‐phosphorylation. In contrast, previous studies on other prion‐like, aggregation‐prone proteins suggest that phosphorylation may be associated with a reduction in self‐association (Li et al , 2011; Tenreiro et al , 2014). …”

The effect of <italic>Scutellaria baicalensis</italic> stem-leaf flavonoids on spatial learning and memory in chronic cerebral ischemia-induced vascular dementia of rats

“…The well-known disease-related epitopes of tau phosphorylation include AT8 (S199/S202/T205), 12E8 (S262/S356), AT180 (T231/ S235), PHF-1 (S396/S404), AT100 (T22/S214/T217), S262, and S422 [45]. It is known that a few enzyme families, especially kinases, play pivotal roles in tau hyperphosphorylation.…”

Poststroke Induction of -Synuclein Mediates Ischemic Brain Damage

“…Under normal conditions, α -Syn predominantly exists in its unphosphorylated form, but oxidative stress and proteasomal dysfunction due to pathologies promote S129 phosphorylation, which is thought to modulate α -Syn oligomerization and aggregation leading to toxicity (Lee and Trojanowski, 2006; Lashuel et al, 2013). While many kinases can mediate phosphorylation of α -Syn, Polo-like kinases (PLK1, 2, and 3) are thought to be the major players (Tenreiro et al, 2014). Ofthose, PLK2 was shown to have an exclusive preference for the α -Syn S129 site.…”