α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity

Ghanem, Simona S.; Majbour, Nour K.; Vaikath, Nishant N.; Ardah, Mustafa T.; Erskine, Daniel; Jensen, Nanna Møller; Fayyad, Muneera; Sudhakaran, Indulekha P.; Vasili, Eftychia; Melachroinou, Katerina; Abdi, Ilham Y.; Poggiolini, Ilaria; Santos, Patrícia; Dorn, Anton Emil; Carloni, Paolo; Vekrellis, Kostas; Attems, Johannes; McKeith, Ian G.; Outeiro, Tiago F.; Jensen, Poul Henning; El‐Agnaf, Omar M. A.

doi:10.1073/pnas.2109617119

Cited by 83 publications

(75 citation statements)

References 60 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, whether phosphorylation at S129 has causal roles in aggregation is not entirely clear [ 4 , 93 ]. Indeed, recent work suggests that phosphorylation of S129 occurs after more mature aggregation of the proteins [ 86 ] and that S129 phosphorylation may decrease aggregation of α-synuclein [ 55 ]. However, our results suggest that STI1 plays a role in vivo in S129 phosphorylation, but also facilitates α-synuclein inclusion deposition.…”

Section: Discussionmentioning

confidence: 99%

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

et al. 2022

View full text Add to dashboard Cite

The predominantly pre-synaptic intrinsically disordered protein α-synuclein is prone to misfolding and aggregation in synucleinopathies, such as Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB). Molecular chaperones play important roles in protein misfolding diseases and members of the chaperone machinery are often deposited in Lewy bodies. Here, we show that the Hsp90 co-chaperone STI1 co-immunoprecipitated α-synuclein, and co-deposited with Hsp90 and Hsp70 in insoluble protein fractions in two mouse models of α-synuclein misfolding. STI1 and Hsp90 also co-localized extensively with filamentous S129 phosphorylated α-synuclein in ubiquitin-positive inclusions. In PD human brains, STI1 transcripts were increased, and in neurologically healthy brains, STI1 and α-synuclein transcripts correlated. Nuclear Magnetic Resonance (NMR) analyses revealed direct interaction of α-synuclein with STI1 and indicated that the STI1 TPR2A, but not TPR1 or TPR2B domains, interacted with the C-terminal domain of α-synuclein. In vitro, the STI1 TPR2A domain facilitated S129 phosphorylation by Polo-like kinase 3. Moreover, mice over-expressing STI1 and Hsp90ß presented elevated α-synuclein S129 phosphorylation accompanied by inclusions when injected with α-synuclein pre-formed fibrils. In contrast, reduced STI1 function decreased protein inclusion formation, S129 α-synuclein phosphorylation, while mitigating motor and cognitive deficits as well as mesoscopic brain atrophy in α-synuclein-over-expressing mice. Our findings reveal a vicious cycle in which STI1 facilitates the generation and accumulation of toxic α-synuclein conformers, while α-synuclein-induced proteostatic stress increased insoluble STI1 and Hsp90.

show abstract

Section: Discussionmentioning

confidence: 99%

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Furthermore, an in vitro study modelling BMAA consumption has demonstrated the structural destabilisation of SOD1 proteins following the substitution of any serine with BMAA, resulting in promotion of neurotoxic SOD1 aggregation [ 130 ]. Similarly, BMAA misincorporation in αSyn is thought to promote protein aggregation via the destabilisation of the extension in Serine 129 phosphorylation [ 123 ], the major posttranslational modification of αSyn aggregation [ 131 ].…”

Section: Alpha-synucleinmentioning

confidence: 99%

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Roberts

Theunissen

Mastaglia

et al. 2022

IJMS

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease classified as both a neurodegenerative and neuromuscular disorder. With a complex aetiology and no current cure for ALS, broadening the understanding of disease pathology and therapeutic avenues is required to progress with patient care. Alpha-synuclein (αSyn) is a hallmark for disease in neurodegenerative disorders, such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy. A growing body of evidence now suggests that αSyn may also play a pathological role in ALS, with αSyn-positive Lewy bodies co-aggregating alongside known ALS pathogenic proteins, such as SOD1 and TDP-43. This review endeavours to capture the scope of literature regarding the aetiology and development of ALS and its commonalities with “synucleinopathy disorders”. We will discuss the involvement of αSyn in ALS and motor neuron disease pathology, and the current theories and strategies for therapeutics in ALS treatment, as well as those targeting αSyn for synucleinopathies, with a core focus on small molecule RNA technologies.

show abstract

“…However, the extent to which these antibodies capture the full spectrum of aSyn pathology has not been systematically investigated. Furthermore, recent findings support a potentially protective effect of aSyn pS129 (Ghanem et al, 2022), and therefore the absence of this modification does not necessarily indicate the absence of aSyn pathology.…”

Section: Introductionmentioning

confidence: 96%

Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases

Altay

Kumar

Burtscher

et al. 2022

Preprint

View full text Add to dashboard Cite

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. An increasing number of studies show that aSyn in pathological aggregates exists as a complex mixture of various post-translationally modified forms and conformations. The distribution of these different species changes during disease progression and varies among the different synucleinopathies. Current approaches for detecting aSyn in human tissues and disease models rely on a limited set of antibodies that have not been thoroughly assessed for their ability to capture the diversity of aSyn proteoforms and aggregation states, and thus are unlikely to provide a complete estimation of aSyn pathology in the brain. To address these challenges, we developed, validated, and characterized an expanded set of antibodies that target different sequences and post-translational modifications (PTMs) along the entire length of aSyn, and recognize all conformations of the protein (monomers, oligomers and fibrils). We demonstrate that the use of multiple antibodies targeting different regions on aSyn is necessary to reveal the heterogeneity of aSyn pathology in human Lewy body disease (LBD) brains, and in neuronal and animal models of aSyn aggregation and inclusion formation. We also present, for the first time, the profiling of aSyn pathology using antibodies against all its key post-translationally modified forms across sporadic and familial LBDs. The antibody validation pipeline we describe here paves the way for a more systematic investigation of the diversity of aSyn pathology in the human brain and peripheral tissues, and in cellular and animal models of synucleinopathies.

show abstract

α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity

Cited by 83 publications

References 60 publications

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

Stress-inducible phosphoprotein 1 (HOP/STI1/STIP1) regulates the accumulation and toxicity of α-synuclein in vivo

Synucleinopathy in Amyotrophic Lateral Sclerosis: A Potential Avenue for Antisense Therapeutics?

Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases

Contact Info

Product

Resources

About