Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies

Szegő, Éva M.; Dominguez-Meijide, Antonio; Gerhardt, Ellen; König, Anika; Koss, David J.; Li, Wen; Pinho, Raquel; Fahlbusch, Christiane; Johnson, Mary Ann; Santos, Patrícia; Villar‐Piqué, Anna; Thom, Tobias; Rizzoli, Silvio O.; Schmitz, Matthias; Li, Jiayi; Zerr, Inga; Attems, Johannes; Jahn, Olaf; Outeiro, Tiago F.

doi:10.1016/j.celrep.2019.06.009

Cited by 48 publications

(67 citation statements)

References 88 publications

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“…Recombinant aSyn was prepared as described before 87 . In brief, pET21-asyn was transformed into competent BL21-DE3 cells (Sigma).…”

Section: Methodsmentioning

confidence: 99%

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Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili²,

König³

et al. 2020

Sci Rep

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Parkinson's disease (PD) and Alzheimer's disease (AD) are common neurodegenerative disorders of the elderly and, therefore, affect a growing number of patients worldwide. Both diseases share, as a common hallmark, the accumulation of characteristic protein aggregates, known as Lewy bodies (LB) in PD, and neurofibrillary tangles in AD. LBs are primarily composed of misfolded α-synuclein (aSyn), and neurofibrillary tangles are primarily composed of tau protein. Importantly, upon pathological evaluation, most AD and PD/Lewy body dementia cases exhibit mixed pathology, with the co-occurrence of both LB and neurofibrillary tangles, among other protein inclusions. Recent studies suggest that both aSyn and tau pathology can spread and propagate through neuronal connections. Therefore, it is important to investigate the mechanisms underlying aggregation and propagation of these proteins for the development of novel therapeutic strategies. Here, we assessed the effects of different pharmacological interventions on the aggregation and internalization of tau and aSyn. We found that anle138b and fulvic acid decrease aSyn and tau aggregation, that epigallocatechin gallate decreases aSyn aggregation, and that dynasore reduces tau internalization. Establishing the effects of small molecules with different chemical properties on the aggregation and spreading of aSyn and tau will be important for the development of future therapeutic interventions.

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“…Recombinant aSyn was prepared as described before 87 . In brief, pET21-asyn was transformed into competent BL21-DE3 cells (Sigma).…”

Section: Methodsmentioning

confidence: 99%

“…Real-time quaking induced conversion (RT-QuiC) was performed as previously reported 87 . In brief, 100 μl of reaction mixtures were pipetted in black 96-well plates per triplicate (Corning Incorporated, Washington, USA).…”

Section: Methodsmentioning

confidence: 99%

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Dominguez-Meijide

Vasili²,

König³

et al. 2020

Sci Rep

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“…Therefore, the possible connection between aSyn and mitochondria has been a topic of interest for several years, with several studies suggesting aSyn may occur within mitochondria (Devi, Raghavendran, Prabhu, Avadhani, & Anandatheerthavarada, ; Martin et al, ; Shavali, Brown‐Borg, Ebadi, & Porter, ). aSyn has also been shown to interact with mitochondrial proteins, such as heat shock protein 10 (Hsp10) (Szego et al, ).…”

Section: The Interactome Of Asynmentioning

confidence: 99%

Synucleinopathies: Where we are and where we need to go

Brás

Dominguez-Meijide

Gerhardt

et al. 2020

Journal of Neurochemistry

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All authors contributed equally to this manuscript. This artic le is relat ed to the Speci al Issue "Synuc lein" Abbreviations: A30P, aSyn substitution of an alanine for a proline at position 30; A53E, aSyn substitution of an alanine for a glutamic acid at position 53; A53T, aSyn substitution of an alanine for a tyrosine at position 53; ALP, autophagy-lysosomal pathway; APLP1, Aβ precursor-like protein 1; aSyn, alpha-synuclein; BiFC, bimolecular fluorescence complementation; CMA, Chaperone-mediated autophagy; CNS, central nervous system; co-IP, co-immunoprecipitation; Cryo-EM, cryo-electron microscopy; CSF, cerebrospinal fluid; Cu, copper; DLB, dementia with Lewy bodies; E46K, aSyn substitution of a glutamic acid for a lysine at position 46; ENS, enteric nervous system; ER, endoplasmic reticulum; Fe, iron; FRET, fluorescence resonance energy transfer; G51D, aSyn substitution of a glycine for a aspartic acid at position 51Abstract Synucleinopathies are a group of disorders characterized by the accumulation of inclusions rich in the a-synuclein (aSyn) protein. This group of disorders includes Parkinson's disease, dementia with Lewy bodies (DLB), multiple systems atrophy, and pure autonomic failure (PAF). In addition, genetic alterations (point mutations and multiplications) in the gene encoding for aSyn (SNCA) are associated with familial forms of Parkinson's disease, the most common synucleinopathy. The Synuclein Meetings are a series that has been taking place every 2 years for about 12 years. The Synuclein Meetings bring together leading experts in the field of Synuclein and related human conditions with the goal of discussing and advancing the research. In 2019, the Synuclein meeting took place in Ofir, a city in the outskirts of Porto, Portugal. The meeting, entitled "Synuclein Meeting 2019:Where we are and where we need to go", brought together >300 scientists studying both clinical and molecular aspects of synucleinopathies. The meeting covered a many of the open questions in the field, in a format that prompted open discussions between the participants, and underscored the need for additional research that, hopefully, will lead to future therapies for a group of as of yet incurable disorders. Here, we provide a summary of the topics discussed in each session and highlight what we know, what we do not know, and what progress needs to be made in order to enable the field to continue to advance. We are confident this systematic assessment of where we stand will be useful to steer the field and contribute to filling knowledge gaps that may form the foundations for future therapeutic strategies, which is where we need to go.

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“…Primary neuronal cultures were prepared from P1-3 C57BL6/J mouse pups of mixed sex. Brie y, after dissection and trypsinisation, dissociated neurons were plated onto poly-L-ornithine (Sigma) coated glass coverslip (100 000 cells per well in 24-well dishes), and maintained in Neurobasal A medium containing B27 (2%, Invitrogen), glutamax (0.5 mM, Invitrogen) and antibiotics [14]. One third of the medium was changed on every third day, and from the second change, no antibiotics was added.…”

Section: Primary Neuronal Culturementioning

confidence: 99%

Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

Szegő¹,

Boß²,

Komnig³

et al. 2020

Preprint

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Background Removing α-synuclein aggregates or preventing their formation constitutes a plausible strategy against Parkinson’s disease (PD). As we recently demonstrated, the β-wrapin protein AS69 binds an N-terminal region in monomeric α-synuclein (aSyn), interferes with fibril nucleation and reduces aSyn aggregates in vitro and in a fruit fly model of A53T aSyn toxicity. Here we tested whether AS69 could also reduce aSyn pathology in mammalian neurons and in mouse brain. Methods Primary mouse neurons were exposed to pre-formed fibrils (PFF) of human WT aSyn or PFF was injected into the striatum of A30P-aSyn transgenic mice to induce aSyn pathology. Densities of phospho-aSyn positive somatic inclusions and dystrophic neurites, degeneration of dopaminergic axon terminals in the striatum and the glial response were determined. Results PFF were readily taken up by primary mouse neurons, and AS69 did not alter PFF uptake. aSyn pathology, as determined by phospho-aSyn staining, was much more pronounced 72 h after PFF addition than after 24 h, and was reduced by AS69. In the striatum, PFF increased aSyn pathology, induced degeneration of dopaminergic axon terminals and glial activation at 90 days after PFF injection. The extent of terminal loss correlated with the density of dystrophic neurites, but not with the number of somatic inclusions. Co-injection of AS69 with PFF abrogated the induction of somatic inclusions and dystrophic neurites, reduced the loss of dopaminergic axon terminals and the reaction of astroglia, but not the effect on microglia. Conclusion AS69, an aSyn monomer-binding protein, reduces aSyn pathology and loss of dopaminergic terminals in primary neurons and in a mouse model. Therefore, our data suggests, that small aSyn-monomer binding proteins, such as AS69, could be promising new therapeutic approaches against Parkinson's disease.

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Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies

Abstract: Highlights d aSyn sequesters HSP10 in the cytosol and prevents it from acting in the mitochondria d Overexpression of HSP10 delays aSyn pathology in vitro and in vivo d HSP10 modulates aSyn pathology in synaptic terminals Authors

Cited by 48 publications

References 88 publications

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Effects of pharmacological modulators of α-synuclein and tau aggregation and internalization

Synucleinopathies: Where we are and where we need to go

Targeting the N-terminus of α-synuclein Monomer Reduces Fibril-induced Aggregation in the Brain

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