Structure and conformational variability of the HER2-trastuzumab-pertuzumab complex.

Single particle analysis from cryogenic transmission electron microscopy (cryo-EM) is particularly attractive for complexes for which structure prediction remains intractable, such as antibody-antigen complexes. Here we obtain the detailed structure of a particularly difficult complex between human epidermal growth factor receptor 2 (HER2) and the antigen-binding fragments from two distinct therapeutic antibodies binding to distant parts of the flexible HER2, pertuzumab and trastuzumab (HTP). We highlight the strengths and limitations of current data processing software in dealing with various kinds of heterogeneities, particularly continuous conformational heterogeneity, and in describing the motions that can be extracted from our dataset. Our HTP structure provides a more detailed view than the one previously available for this ternary complex. This allowed us to pinpoint a previously overlooked loop in domain IV that may be involved both in binding of trastuzumab and in HER2 dimerization. This finding may contribute to explain the synergistic anticancer effect of the two antibodies. We further propose that the flexibility of the HTP complex, beyond the difficulties it causes for cryo-EM analysis, actually reflects regulation of HER2 signaling and its inhibition by therapeutic antibodies. Notably we obtain our best data with ultra-thin continuous carbon grids, showing that with current cameras their use to alleviate particle misdistribution is compatible with a protein complex of only 162 kDa. Perhaps most importantly, we provide here a dataset for such a smallish protein complex for further development of software accounting for continuous conformational heterogeneity in cryo-EM images.

Removal of Unwanted Hair: Efficacy and Safety of 755-nm Alexandrite Laser Equipped with a 30 mm Spot Handpiece.

Background: Alexandrite 755 nm laser has been currently recognized one of the gold standards for the permanent hair removal business because of its sufficient tissue penetration and higher affinity for melanin compared with Nd:YAG, making the treatment more incisive and effective. Objective: In this study, we evaluated an Alexandrite 755 nm laser with a 30-mm spot for a new and fast hair removal treatment. Methods: Patients of both genders, with skin Fitzpatrick's types, ranging from II to III, were asked to avoid any epilation techniques 4 weeks before the laser hair removal session. Participants underwent a minimum of three to a maximum of eight sessions of treatment, every 6 weeks. Six months after the last treatment, the final evaluation was completed. The treated body areas included arms, legs, axillae, and trunk. The subjects used a numeric scale with a range of 0 to 10 (0: no pain, 10: unbearable), to indicate the associated pain level experienced. By comparing the percentage of terminal hairs before and after laser treatment, hair reduction was determined. Results: The patients reported only slight post-treatment erythema that disappeared after a few hours and only two patients showed persistent erythema lasting a few weeks. The pain was found to be 4.9 ± 0.9 after single pass emission. Conclusions: The 755 nm laser with the new handpiece has proven to be an ideal wavelength for hair removal, allowing efficient, safe, and faster treatments to be performed for the patient.

Novel Management of Granuloma Formation Secondary to Dermal Filler with Intralesional 1444 nm Nd:YAG Laser Technique.

Background: Dermal fillers for soft tissue for the treatment of face sagging, volume loss, and wrinkles have become popular among patients of all ages and ethnicities, and their use is becoming increasingly widespread. Aim: the goal of this study was to evaluate the effectiveness and safety of a micro-pulsed, 1444 nm Nd:YAG laser on dermal filler complications, in particular on granuloma management. Methods: A subcutaneous, 1444 nm Nd:YAG laser was used on five female patients (range age 52-68 years) with hyaluronic filler granulomas located on the face (two on the cheek area and three on the lips); three patients had self-injected the filler, buying it online. Before and after the therapy, the patients received a skin ultrasound to determine the form and location of the granulomas and to determine if there had been a full or partial resolution. During this study, all possible adverse effects at the treatment site were monitored. The 5-point Global Aesthetic Improvement Scale (GAIS) (0 point-no change; 1 point-25%, mild improvement; 2 points-50%, moderate improvement; 3 points-75%, good improvement; 4 points-100%, excellent improvement) was recorded at a 3-month follow-up. Results: good results were obtained in the treatment of filler granulomas with the intralesional 1444 nm laser, even if just a single treatment was performed (one intervention was effective for curing granulomas up to 5 mm in diameter). Three patients were satisfied with excellent improvement, and two patients experienced good improvement. The results are functional and aesthetically satisfying, as shown by photographic assessment. At the last follow-up, the granuloma had reduced or completely disappeared in all cases, and no infections, burns, scarring or fibrosis, episodes of severe bleeding, or other serious adverse effects had been reported. All subjects tolerated the post-treatment period well. Conclusions: Our findings showed that granuloma treatment with an intralesional 1444 nm Nd:YAG laser is a minimally invasive, easy, fast, efficient, and low-risk procedure.

A proteome scale study reveals how plastic surfaces and agitation promote protein aggregation.

Protein aggregation in biotherapeutics can reduce their activity and effectiveness. It may also promote immune reactions responsible for severe adverse effects. The impact of plastic materials on protein destabilization is not totally understood. Here, we propose to deconvolve the effects of material surface, air/liquid interface, and agitation to decipher their respective role in protein destabilization and aggregation. We analyzed the effect of polypropylene, TEFLON, glass and LOBIND surfaces on the stability of purified proteins (bovine serum albumin, hemoglobin and α-synuclein) and on a cell extract composed of 6000 soluble proteins during agitation (P = 0.1-1.2 W/kg). Proteomic analysis revealed that chaperonins, intrinsically disordered proteins and ribosomes were more sensitive to the combined effects of material surfaces and agitation while small metabolic oligomers could be protected in the same conditions. Protein loss observations coupled to Raman microscopy, dynamic light scattering and proteomic allowed us to propose a mechanistic model of protein destabilization by plastics. Our results suggest that protein loss is not primarily due to the nucleation of small aggregates in solution, but to the destabilization of proteins exposed to material surfaces and their subsequent aggregation at the sheared air/liquid interface, an effect that cannot be prevented by using LOBIND tubes. A guidance can be established on how to minimize these adverse effects. Remove one of the components of this combined stress - material, air (even partially), or agitation - and proteins will be preserved.

Lipoma management with a minimally invasive 1,444 nm Nd:YAG laser technique.

Background: Lipoma is the most common benign mesenchymal tumor that is composed of mature fat cells. Subdermal laser lipoma treatment may be recommended as an alternative to surgery for its removal. Purpose: The purpose of the study was to investigate the efficacy of the 1,444 nm Nd:YAG laser subcutaneous intralesional application as a treatment option for lipoma. Materials and methods: On 60 patients (37 women and 23 men) with lipomas localized above the muscle and lipomatosis in various regions, a subcutaneous, micro-pulsed 1,444 nm Nd:YAG laser procedure was executed. Before treatment, an ultrasound was performed and the lipomas were measured. The same lighting setup and photographic tools were used to take pictures of each patient. Results: The lipoma reduced or completely disappeared in all cases at the last follow-up, and no infections, burns, skin lesions, episodes of severe bleeding, or other serious adverse effects were reported. The most common transient side effects were ecchymosis and edema. Partial lesion reduction refers to rare cases of lipomatosis in which the lipomas were so small that suction and accurate positioning of the capsular membrane contours were impossible. Conclusion: Lipoma treatment with a 1,444 nm Nd:YAG laser is a safe and effective minimally invasive procedure without risk of scarring. For cellular disruption, laser treatment is an effective and safe option.

Skin Fractional Scar Treatment with a New Carbon Dioxide Scanner: Histological and Clinical Evaluation.

Background: The mechanism of action of fractional carbon dioxide (CO2) laser in the management of skin scarring is stimulation of collagen and fibroblasts in the dermis, resulting in remodeling and shrinking of the skin. Objective: The purpose of this research is to assess the safety and performance of a new CO2 laser scanner for treatment of acne scars. Methods: The study was carried out on 20 patients of both sexes, with a mean age of 25.7 ± 6.7 years. To assess the performance and safety of this new CO2 scanner, a preclinical histological evaluation was done. A clinical evaluation of acne scars was performed using Goodman and Baron's quantitative global acne scarring grading system (GBQGASGS) and a crusting scale where crusting scores ranged from 1 = none to 4 = severe. Digital photographs were taken to obtain esthetic results. Results: GBQGASGS showed a significant improvement in patients' scars and the treatment was well tolerated, with no lasting side effects. Conclusions: The new scanner seems to be an effective and safe device for skin scarring treatment, speeding up the healing time of scars.

Atomic structure of Lanreotide nanotubes revealed by cryo-EM.

Functional and versatile nano- and microassemblies formed by biological molecules are found at all levels of life, from cell organelles to full organisms. Understanding the chemical and physicochemical determinants guiding the formation of these assemblies is crucial not only to understand the biological processes they carry out but also to mimic nature. Among the synthetic peptides forming well-defined nanostructures, the octapeptide Lanreotide has been considered one of the best characterized, in terms of both the atomic structure and its self-assembly process. In the present work, we determined the atomic structure of Lanreotide nanotubes at 2.5-Å resolution by cryoelectron microscopy (cryo-EM). Surprisingly, the asymmetric unit in the nanotube contains eight copies of the peptide, forming two tetramers. There are thus eight different environments for the peptide, and eight different conformations in the nanotube. The structure built from the cryo-EM map is strikingly different from the molecular model, largely based on X-ray fiber diffraction, proposed 20 y ago. Comparison of the nanotube with a crystal structure at 0.83-Å resolution of a Lanreotide derivative highlights the polymorphism for this peptide family. This work shows once again that higher-order assemblies formed by even well-characterized small peptides are very difficult to predict.

Could 675-nm Laser Treatment Be Effective for Facial Melasma Even in Darker Phototype?

Objective: The study assesses the safety and efficacy of a 675-nm laser source on melasma. Background: Melasma is a frequent acquired skin disease defined by the presence of hyperpigmented macules on the face. Methods: Study protocol included up to three sessions of the 675-nm laser. Objective evaluation was assessed by using a 5-point visual analogue pain scale (VAS) (range, 0-4). Treatment tolerance was assessed using the 5-point VAS. Results: A mean 3.1 ± 0.7 improvement was reached according to photographic evaluation by VAS. Patients treated one time showed mean clearance of 3.3 ± 0.76, patients treated two times showed mean clearance of 3.0 ± 0.71, and patients treated three times showed mean clearance of 3.0 ± 1. Pain score mean was 1.2 ± 0.4. Conclusions: The 675-nm laser system seems to be safe and effective even in the treatment of facial melasma in patients with Fitzpatrick phototypes IV to V.

Histological Skin Changes After Treatment with 675 nm Laser.

Objective: To evaluate the histological effects of a new 675-nm laser device on the skin. Background: Innovative technologies based on physical principles have been proposed in recent years to improve the treatment of aging skin. Laser technology is currently being studied for its potential in skin care treatments. A new 675-nm laser device is being used for the treatment of hyperpigmentation, scars, and various types of wrinkles. Methods: A 42-year-old man underwent a 675-nm RedTouch® laser session for the treatment of aging signs on the neck. Two 2.5-mm biopsies were taken from the treated area and the adjacent area untreated with the laser, 45 days after the procedure. Comparison of the immunohistochemistry findings and assessment of the collagen and elastin fibers were performed by a board-certified dermatopathologist. Results: Skin biopsies revealed histological changes that comprised proliferation of new collagen fibers in the treated area, when compared to that in the untreated areas. Conclusions: Histological analysis suggests that the 675-nm laser has a potential role in stimulating collagen remodeling, with a significant increase in thin and new collagen fibers.

Ridge Preservation Using an Innovative Enzyme-deantigenic Equine Bone Paste: A Case Report with 36-month Follow-up.

AIM: This study aimed to report a successful clinical, histological, and histomorphometric outcome of a novel equine-derived bone paste for a ridge preservation surgery involving a single post-extractive socket. BACKGROUND: After tooth avulsion, unless the implant position is not carried out straightforwardly, the alveolar process undergoes resorption: to limit it, post-extractive sockets may be grafted according to the ridge preservation principles. Grafting materials should display proper biological properties and optimal handling characteristics. Bone pastes may facilitate grafting operations, avoid granules' dispersion, and maximize the contact of the graft with the surrounding bone. An innovative equine-derived bone paste has been recently introduced on the market, but its use has never been documented in the medical literature. CASE DESCRIPTION: This report describes the treatment of a patient who received the equine-derived bone paste in a post-extractive socket to allow the preservation of the alveolar ridge and was later rehabilitated with a crown supported by a single implant. CONCLUSION: The handling properties of the equine-derived bone paste were excellent. At the 36-month follow-up, the peri-implant bone levels had been maintained, with the implant being successful according to the Albrektsson and Zarb criteria. Histologic outcome showed that the bone paste was fully biocompatible; histomorphometric analysis showed that a significant amount of newly formed bone could be observed in the grafted socket. CLINICAL SIGNIFICANCE: Alveolar ridge preservation using bone grafts is a well-known approach, yet there is still no agreement about which bone graft might be considered the most suitable for this indication. The novel equine-derived bone paste used in the present study appears a promising option for effective socket preservation and may promote secondary intention healing. How to cite this article: Di Stefano DA, Arosio P, Cinci L, et al. Ridge Preservation Using an Innovative Enzyme-deantigenic Equine Bone Paste: A Case Report with 36-month Follow-up. J Contemp Dent Pract 2019;20(10):1229-1234.

Clustering of Tau fibrils impairs the synaptic composition of α3-Na+/K+-ATPase and AMPA receptors.

Tau assemblies have prion-like properties: they propagate from one neuron to another and amplify by seeding the aggregation of endogenous Tau. Although key in prion-like propagation, the binding of exogenous Tau assemblies to the plasma membrane of naïve neurons is not understood. We report that fibrillar Tau forms clusters at the plasma membrane following lateral diffusion. We found that the fibrils interact with the Na+/K+-ATPase (NKA) and AMPA receptors. The consequence of the clustering is a reduction in the amount of α3-NKA and an increase in the amount of GluA2-AMPA receptor at synapses. Furthermore, fibrillar Tau destabilizes functional NKA complexes. Tau and α-synuclein aggregates often co-exist in patients' brains. We now show evidences for cross-talk between these pathogenic aggregates with α-synuclein fibrils dramatically enhancing fibrillar Tau clustering and synaptic localization. Our results suggest that fibrillar α-synuclein and Tau cross-talk at the plasma membrane imbalance neuronal homeostasis.

Socket Preservation using Enzyme-treated Equine Bone Granules and an Equine Collagen Matrix: A Case Report with Histological and Histomorphometrical Assessment.

AIM: To histologically assess the effectiveness of a socket-preservation technique using enzyme-treated equine bone granules as a bone-graft material in combination with an equine collagen matrix as a scaffold for soft-tissue regeneration. BACKGROUND: Enzyme-treated equine bone granules and equine collagen matrix recently have been developed to help overcome alveolar bone deficiencies that develop in the wake of edentulism. CASE REPORT: The patient had one mandibular molar extracted and the socket grafted with equine bone granules. The graft was covered with the equine collagen matrix, placed in a double layer. No flap was prepared, and the gingival margins were stabilized with a single stitch, leaving the matrix partially exposed and the site to heal by secondary intention. The adjacent molar was extracted 1 month later, and that socket was left to heal by secondary intention without any further treatment. Three months after each surgery, an implant was placed and a biopsy was collected. The two biopsies underwent histological processing and qualitative evaluation. Histomorphometric analysis was also performed to calculate the percentage of newly formed bone (NFB) in the two cores. Healing at both sites was uneventful, and no inflammation or other adverse reactions were observed in the samples. Soft-tissue healing by secondary intention appeared to occur faster at the grafted site. The corresponding core showed a marked separation between soft and hard tissue that was not observed in the core from the nongrafted site, where soft-tissue hypertrophy could be observed. Newly formed bone at the grafted and nongrafted sites was not significantly different (27.2 ± 7.1 and 29.4 ± 6.2% respectively, p = 0.45). CONCLUSION: The surgical technique employed in this case appeared to facilitate postextraction soft-tissue healing by second intention and simplify soft-tissue management. CLINICAL SIGNIFICANCE: Using a collagen-based matrix to cover a postextraction grafted site may facilitate second intention soft-tissue healing and proper soft-tissue growth.

Structural and functional properties of prefibrillar α-synuclein oligomers.

The deposition of fibrillar alpha-synuclein (α-syn) within inclusions (Lewy bodies and Lewy neurites) in neurons and glial cells is a hallmark of synucleinopathies. α-syn populates a variety of assemblies ranging from prefibrillar oligomeric species to fibrils whose specific contribution to neurodegeneration is still unclear. Here, we compare the specific structural and biological properties of distinct soluble prefibrillar α-syn oligomers formed either spontaneously or in the presence of dopamine and glutaraldehyde. We show that both on-fibrillar assembly pathway and distinct dopamine-mediated and glutaraldehyde-cross-linked α-syn oligomers are only slightly effective in perturbing cell membrane integrity and inducing cytotoxicity, while mature fibrils exhibit the highest toxicity. In contrast to low-molecular weight and unstable oligomers, large stable α-syn oligomers seed the aggregation of soluble α-syn within reporter cells although to a lesser extent than mature α-syn fibrils. These oligomers appear elongated in shape. Our findings suggest that α-syn oligomers represent a continuum of species ranging from unstable low molecular weight particles to mature fibrils via stable elongated oligomers composed of more than 15 α-syn monomers that possess seeding capacity.

Bone Formation Following Sinus Augmentation with an Equine-Derived Bone Graft: A Retrospective Histologic and Histomorphometric Study with 36-Month Follow-up.

PURPOSE: The aim of this study was to investigate bone formation over time following maxillary sinus augmentation with an enzyme-deantigenic, bone collagen-preserving equine bone graft by retrospective assessment of histomorphometric data. MATERIALS AND METHODS: Records of patients with atrophic ridges who underwent maxillary sinus augmentation with the enzyme-deantigenic equine bone graft and two-step implant placement between 3 and 12 months after the sinus-augmentation surgery were assessed retrospectively. The histomorphometric data were clustered in three classes according to time of collection from the augmentation surgery and analyzed to assess newly formed bone deposition and residual biomaterial degradation rates. Data concerning the 36-month clinical follow-up were also assessed. RESULTS: Records of 77 patients and 115 biopsy specimens were retrieved, and histomorphometric data were clustered (3 to 5 months, n = 33; 6 to 8 months, n = 57; 9 to 12 months, n = 25). Mean minimum atrophic ridge thickness was 4.9 ± 0.5 mm (range, 4.0 to 7.1 mm). The amount of newly formed bone and residual biomaterial did not significantly differ among the three clusters. Qualitative analysis showed a denser trabecular structure in late (> 8 months) samples. At the 36-month clinical follow-up, no differences were found among the implant success rates in the three groups, according to the Albrektsson and Zarb criteria for success. The overall implant success rate was 98.3%. CONCLUSION: Based upon this retrospective human study of 77 patients with 4 to 7 mm of residual bone, when enzyme-deantigenic equine bone is used for sinus augmentation, new bone formation occurs at an early time (< 3 months) after the grafting, and implant placement can be safely carried out as soon as 3 to 5 months after the augmentation surgery.

Cellular response of human neuroblastoma cells to α-synuclein fibrils, the main constituent of Lewy bodies.

BACKGROUND: α-Synuclein (α-Syn) fibrils are the main constituent of Lewy bodies and a neuropathological hallmark of Parkinson's disease (PD). The propagation of α-Syn assemblies from cell to cell suggests that they are involved in PD progression. We previously showed that α-Syn fibrils are toxic because of their ability to bind and permeabilize cell membranes. Here, we document the cellular response in terms of proteome changes of SH-SY5Y cells exposed to exogenous α-Syn fibrils. METHODS: We compare the proteomes of cells of neuronal origin exposed or not either to oligomeric or fibrillar α-Syn using two dimensional differential in-gel electrophoresis (2D-DIGE) and mass spectrometry. RESULTS: Only α-Syn fibrils induce significant changes in the proteome of SH-SY5Y cells. In addition to proteins associated to apoptosis and toxicity, or proteins previously linked to neurodegenerative diseases, we report an overexpression of proteins involved in intracellular vesicle trafficking. We also report a remarkable increase in fibrillar α-Syn heterogeneity, mainly due to C-terminal truncations. CONCLUSIONS: Our results show that cells of neuronal origin adapt their proteome to exogenous α-Syn fibrils and actively modify those assemblies. GENERAL SIGNIFICANCE: Cells of neuronal origin adapt their proteome to exogenous toxic α-Syn fibrils and actively modify those assemblies. Our results bring insights into the cellular response and clearance events the cells implement to face the propagation of α-Syn assemblies associated to pathology.

α-synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient.

Extracellular α-synuclein (α-syn) assemblies can be up-taken by neurons; however, their interaction with the plasma membrane and proteins has not been studied specifically. Here we demonstrate that α-syn assemblies form clusters within the plasma membrane of neurons. Using a proteomic-based approach, we identify the α3-subunit of Na+/K+-ATPase (NKA) as a cell surface partner of α-syn assemblies. The interaction strength depended on the state of α-syn, fibrils being the strongest, oligomers weak, and monomers none. Mutations within the neuron-specific α3-subunit are linked to rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). We show that freely diffusing α3-NKA are trapped within α-syn clusters resulting in α3-NKA redistribution and formation of larger nanoclusters. This creates regions within the plasma membrane with reduced local densities of α3-NKA, thereby decreasing the efficiency of Na+ extrusion following stimulus. Thus, interactions of α3-NKA with extracellular α-syn assemblies reduce its pumping activity as its mutations in RDP/AHC.

Histomorphometric Comparison of Enzyme-Deantigenic Equine Bone and Anorganic Bovine Bone in Sinus Augmentation: A Randomized Clinical Trial with 3-Year Follow-Up.

PURPOSE: To conduct a histomorphometric investigation comparing the use of enzyme-deantigenic equine bone (EDEB) and anorganic bovine bone (ABB) for maxillary sinus augmentation. MATERIALS AND METHODS: Forty patients with Cawood Class V atrophic ridges who required maxillary sinus augmentation randomly received EDEB (n = 20) or ABB (n = 20) granules. Six months later, biopsy specimens were obtained, and implants were placed. Bone specimens were subjected to histomorphometric analysis, and newly formed bone (NFB) and residual biomaterial (RB) percentages were calculated. Patients were followed up for 3 years after definitive prosthetic rehabilitation, and implant success and survival rates were determined according to the criteria of Albrektsson and Zarb. RESULTS: All patients healed uneventfully. Histomorphometric results for the EDEB were as follows: NFB = 46.86% ± 12.81% and RB = 11.05% ± 9.27%. For ABB, they were: NFB = 25.12% ± 7.25% and RB = 28.65% ± 9.70%. The difference was significant at a .05 level of confidence both for NFB and RB. At the 3-year follow-up, the implant survival rate was identical in the two groups (100%). CONCLUSION: Grafting with EDEB resulted in a greater quantity of NFB at implant insertion. No significant clinical differences were observed between the two patient groups at the 3-year follow-up. EDEB was as effective as ABB for sinus augmentation.

Horizontal-guided Bone Regeneration using a Titanium Mesh and an Equine Bone Graft.

AIM: The present work describes a horizontal ridge augmentation in which a titanium mesh was preshaped by adapting it to a stereolithographic model of the patient's jaw that was fabricated from CT scans. BACKGROUND: Guided bone regeneration (GBR) involves covering the augmentation site with a long-lasting barrier to protect it from the invasion of surrounding soft tissues. Among barriers, titanium meshes may provide a successful outcome, but the intraoperatory time needed to shape them is a disadvantage. CASE DESCRIPTION: The 54-year-old patient, missing the right mandibular second bicuspid, first molar, and second molar, had her atrophic ridge augmented with a 30:70 mixture of autogenous bone and equine, enzyme-deantigenic collagen-preserved bone substitute. Two conical implants were inserted concomitantly in the second bicuspid and first molar positions, and the site was protected with the preshaped mesh. Four months later, the titanium mesh was retrieved, a bone sample was collected, and histological and histomorphometric analyses were performed. Provisional and definitive prostheses were then delivered, and follow-up controls were performed for up to 24 months. CONCLUSION: Preshaping the mesh on a model of the patient's mandible shortened the surgical time and enabled faster mesh placement. Two years after surgery, the implants were perfectly functional, and the bone width was stable over time as shown by radiographic controls. Histological analysis of the bone sample showed the heterologous biomaterial to be biocompatible and undergoing advanced remodeling and replacement with newly formed bone. CLINICAL SIGNIFICANCE: Preshaping a titanium mesh over a stereolithographic model of the patient's jaw allowed for a significant reduction of the intraoperative time and may be therefore, advisable in routine practice.

Structural and functional characterization of two alpha-synuclein strains.

α-Synuclein aggregation is implicated in a variety of diseases including Parkinson's disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.