In Lewy body diseases-including Parkinson's disease, without or with dementia, dementia with Lewy bodies, and Alzheimer's disease with Lewy body co-pathology
-α-synuclein (α-Syn) aggregates in ...neurons as Lewy bodies and Lewy neurites
. By contrast, in multiple system atrophy α-Syn accumulates mainly in oligodendrocytes as glial cytoplasmic inclusions (GCIs)
. Here we report that pathological α-Syn in GCIs and Lewy bodies (GCI-α-Syn and LB-α-Syn, respectively) is conformationally and biologically distinct. GCI-α-Syn forms structures that are more compact and it is about 1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of multiple system atrophy. GCI-α-Syn and LB-α-Syn show no cell-type preference in seeding α-Syn pathology, which raises the question of why they demonstrate different cell-type distributions in Lewy body disease versus multiple system atrophy. We found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting the fact that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.
Identification of multiple immune-related genetic risk factors for sporadic AD (sAD) have put the immune system center stage in mechanisms underlying this disorder. Comprehensive analysis of ...microglia in different stages of AD in human brains revealed microglia activation to follow the progression of AD neuropathological changes and requiring the co-occurrence of beta-Amyloid (Aβ) and tau pathology. Carriers of AD-associated risk variants in TREM2 (Triggering receptor expressed on myeloid cells 2) showed a reduction of plaque-associated microglia and a substantial increase in dystrophic neurites and overall pathological tau compared with age and disease stage matched AD patients without TREM2 risk variants. These findings were substantiated by digital spatial profiling of the plaque microenvironment and targeted gene expression profiling on the NanoString nCounter system, which revealed striking brain region dependent differences in immune response patterns within individual cases. The demonstration of profound brain region and risk-variant specific differences in immune activation in human AD brains impacts the applicability of immune-therapeutic approaches for sAD and related neurodegenerative diseases.
The accumulation and propagation of misfolded α-synuclein (α-Syn) is a central feature of Parkinson’s disease and other synucleinopathies. Molecular compatibility between a fibrillar seed and its ...native protein state is a major determinant of amyloid self-replication. We show that cross-seeded aggregation of human (Hu) and mouse (Ms) α-Syn is bidirectionally restricted. Although fibrils formed by Hu-Ms-α-Syn chimeric mutants can overcome this inhibition in cell-free systems, sequence homology poorly predicts their efficiency in inducing α-Syn pathology in primary neurons or after intracerebral injection into wild-type mice. Chimeric α-Syn fibrils demonstrate enhanced or reduced pathogenicities compared with wild-type Hu- or Ms-α-Syn fibrils. Furthermore, α-Syn mutants induced to polymerize by fibrillar seeds inherit the functional properties of their template, suggesting that transferable pathogenic and non-pathogenic states likely influence the initial engagement between exogenous α-Syn seeds and endogenous neuronal α-Syn. Thus, transmission of synucleinopathies is regulated by biological processes in addition to molecular compatibility.
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•Alpha-Synuclein (α-Syn) cross-seeding is less efficient than homologous seeding•Sequence homology between α-Syn monomers and fibril seeds predicts seeding in vitro•Chimeric α-Syn fibrils vary greatly in their ability to induce pathology in neurons•Pathogenicity of α-Syn fibrils can be templated to non-homologous α-Syn monomers
Luk et al. show that cross-seeding between human (Hu) and mouse (Ms) α-synuclein (α-Syn) is less efficient than homologous seeding. Using a series of Hu-Ms chimeric proteins, they show that these fibrils likely adopt distinct and transferable configurations that determine the ability to induce Parkinson’s disease-like pathology in neurons and in vivo.
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases for which there is no disease-modifying treatment. PD and DLB are characterized by aggregation ...of the synaptic protein α-synuclein, and there is compelling evidence to suggest that progression of these diseases is associated with the trans-cellular spread of pathogenic α-synuclein through the brains of afflicted individuals. Therapies targeting extracellular, pathogenic α-synuclein may therefore hold promise for slowing or halting disease progression. In this regard, it has been suggested that highly-selective antibodies can be administered as therapeutic agents targeting pathogenic proteins. In the current study, we screened a series of antibodies using multiple selection criterion to identify those that selectively bind pathogenic α-synuclein and show potent inhibition of pathology seeding in a neuronal model of α-synucleinopathy. A lead antibody was tested in a mouse model of PD, and it was able to reduce the spread of α-synuclein pathology in the brain and attenuate dopamine reductions in the striatum. This study highlights the therapeutic potential of α-synuclein immunotherapy for the treatment of PD and DLB, and provides a framework for screening of α-synuclein antibodies to identify those with preferred properties.
•Conformation selective antibodies have less potential for off-target effects.•Inoculation of mice with misfolded α-synuclein generated a new class of antibodies.•Multi-assay screening identified highly selective and potent antibodies.•Lead antibody reduces α-synuclein pathology and improves dopamine in vivo.
Botulinum neurotoxins (BoNTs) are classified into seven types (A-G), but multiple subtype and mosaic toxins exist. These subtype and mosaic toxins share a high sequence identity, and presumably the ...same receptors and substrates with their parental toxins. Here, we report that a mosaic toxin, type D-C (BoNT/D-C), uses different receptors from its parental toxin BoNT/C. BoNT/D-C, but not BoNT/C, binds directly to the luminal domains of synaptic vesicle proteins synaptotagmin (Syt) I and II, and requires expression of SytI/II to enter neurons. The SytII luminal fragment containing the toxin-binding site can block the entry of BoNT/D-C into neurons and reduce its toxicity in vivo in mice. We also found that gangliosides increase binding of BoNT/D-C to SytI/II and enhance the ability of the SytII luminal fragment to block BoNT/D-C entry into neurons. These data establish SytI/II, in conjunction with gangliosides, as the receptors for BoNT/D-C, and indicate that BoNT/D-C is functionally distinct from BoNT/C. We further found that BoNT/D-C recognizes the same binding site on SytI/II where BoNT/B and G also bind, but utilizes a receptor-binding interface that is distinct from BoNT/B and G. Finally, we also report that human and chimpanzee SytII has diminished binding and function as the receptor for BoNT/B, D-C and G owing to a single residue change from rodent SytII within the toxin binding site, potentially reducing the potency of these BoNTs in humans and chimpanzees.
We report results of a search for an isotropic gravitational-wave background (GWB) using data from Advanced LIGO's and Advanced Virgo's third observing run (O3) combined with upper limits from the ...earlier O1 and O2 runs. Unlike in previous observing runs in the advanced detector era, we include Virgo in the search for the GWB. The results of the search are consistent with uncorrelated noise, and therefore we place upper limits on the strength of the GWB. We find that the dimensionless energy density Ω(sub GW) ≤ 5.8 × 10(exp -9) at the 95% credible level for a at (frequency-independent) GWB, using a prior which is uniform in the log of the strength of the GWB, with 99% of the sensitivity coming from the band 20-76.6 Hz; Ω(sub GW)(f) ≤ 3.4 × 10(exp -9) at 25 Hz for a power-law GWB with a spectral index of 2/3 (consistent with expectations for compact binary coalescences), in the band 20-90.6 Hz; and Ω(sub GW)(f) ≤ 3.9 × 10(exp -10) at 25 Hz for a spectral index of 3, in the band 20-291.6 Hz. These upper limits improve over our previous results by a factor of 6.0 for a at GWB, 8.8 for a spectral index of 2/3, and 13.1 for a spectral index of 3. We also search for a GWB arising from scalar and vector modes, which are predicted by alternative theories of gravity; we do not find evidence of these, and place upper limits on the strength of GWBs with these polarizations. We demonstrate that there is no evidence of correlated noise of magnetic origin by performing a Bayesian analysis that allows for the presence of both a GWB and an effective magnetic background arising from geophysical Schumann resonances. We compare our upper limits to a fiducial model for the GWB from the merger of compact binaries, updating the model to use the most recent data-driven population inference from the systems detected during O3a. Finally, we combine our results with observations of individual mergers and show that, at design sensitivity, this joint approach may yield stronger constraints on the merger rate of binary black holes at z ≳ 2 than can be achieved with individually resolved mergers alone.
We report on gravitational wave discoveries from compact binary coalescences detected by Advanced LIGO and Advanced Virgo in the first half of the third observing run (O3a) between 1 April 2019 15:00 ...UTC and 1 October 2019 15:00 UTC. By imposing a false-alarm-rate threshold of two per year in each of the four search pipelines that constitute our search, we present 39 candidate gravitational wave events. At this threshold, we expect a contamination fraction of less than 10%. Of these, 26 candidate events were reported previously in near real-time through GCN Notices and Circulars; 13 are reported here for the first time. The catalog contains events whose sources are black hole binary mergers up to a redshift of ~ 0.8, as well as events whose components could not be unambiguously identified as black holes or neutron stars. For the latter group, we are unable to determine the nature based on estimates of the component masses and spins from gravitational wave data alone. The range of candidate event masses which are unambiguously identified as binary black holes (both objects ≥ 3 M⨀) is increased compared to GWTC-1, with total masses from ∼ 14M⨀ for GW190924 021846 to ∼ 150M⨀ for GW190521. For the first time, this catalog includes binary systems with significantly asymmetric mass ratios, which had not been observed in data taken before April 2019. We also find that 11 of the 39 events detected since April 2019 have positive effective inspiral spins under our default prior (at 90% credibility), while none exhibit negative effective inspiral spin. Given the increased sensitivity of Advanced LIGO and Advanced Virgo, the detection of 39 candidate events in ∼26 weeks of data (∼1.5 per week) is consistent with GWTC-1.
We search for gravitational-wave signals produced by cosmic strings in the Advanced LIGO and Virgo full O3 dataset. Search results are presented for gravitational waves produced by cosmic string loop ...features such as cusps, kinks, and, for the first time, kink-kink collisions. A template-based search for short-duration transient signals does not yield a detection. We also use the stochastic gravitational-wave background energy density upper limits derived from the O3 data to constrain the cosmic string tension Gμ as a function of the number of kinks, or the number of cusps, for two cosmic string loop distribution models. Additionally, we develop and test a third model that interpolates between these two models. Our results improve upon the previous LIGO–Virgo constraints on Gμ by 1 to 2 orders of magnitude depending on the model that is tested. In particular, for the one-loop distribution model, we set the most competitive constraints to date: Gμ ≲ 4×10−15. In the case of cosmic strings formed at the end of inflation in the context of grand unified theories, these results challenge simple inflationary models.
We report results from searches for anisotropic stochastic gravitational-wave backgrounds using data from the first three observing runs of the Advanced LIGO and Advanced Virgo detectors. For the ...first time, we include Virgo data in our analysis and run our search with a new efficient pipeline called PyStochon data folded over one sidereal day. We use gravitational-wave radiometry(broadband and narrow band) to produce sky maps of stochastic gravitational-wave backgrounds and to search for gravitational waves from point sources. A spherical harmonic decomposition method is employed to look for gravitational-wave emission from spatially-extended sources. Neither technique found evidence of gravitational-wave signals. Hence we derive 95% confidence-level upper limit sky maps on the gravitational-wave energy flux from broadband point sources, ranging from F(α,Θ) < (0.013−7.6)×10^(−8)erg/sq. cm s Hz,and on the (normalized) gravitational-wave energy density spectrum from extended sources, ranging from Ω(α,Θ) < (0.57−9.3)×10^(−9) per sr, depending on direction (Θ) and spectral index (α). These limits improve upon previous limits by factors of 2.9−3.5. We also set 95% confidence level upper limits on the frequency-dependent strain amplitudes of quasimonochromatic gravitational waves coming from three interesting targets, Scorpius X-1, SN1987A and the Galactic Center, with best upper limits range fromh(0) < (1.7−2.1)×10^(−25), a factor of ≥ 2.0 improvement compared to previous stochastic radiometer searches.
Here, we present a search for subsolar mass ultracompact objects in data obtained during Advanced LIGO's second observing run. In contrast to a previous search of Advanced LIGO data from the first ...observing run, this search includes the effects of component spin on the gravitational waveform. We identify no viable gravitational-wave candidates consistent with subsolar mass ultracompact binaries with at least one component between $0.2 M_{⊙}-1.0 M_{⊙}$. We use the null result to constrain the binary merger rate of ($0.2 M_{⊙}, 0.2 M_{⊙}$) binaries to be less than $3.7×10^{5} Gpc^{-3} yr^{-1}$ and the binary merger rate of ($1.0 M_{⊙}, 1.0 M_{⊙}$) binaries to be less than $5.2×10^{3} Gpc^{-3} yr^{-1}$. Subsolar mass ultracompact objects are not expected to form via known stellar evolution channels, though it has been suggested that primordial density fluctuations or particle dark matter with cooling mechanisms and/or nuclear interactions could form black holes with subsolar masses. Assuming a particular primordial black hole (PBH) formation model, we constrain a population of merging $0.2 M_{⊙}$ black holes to account for less than 16% of the dark matter density and a population of merging $1.0 M_{⊙}$ black holes to account for less than 2% of the dark matter density. We discuss how constraints on the merger rate and dark matter fraction may be extended to arbitrary black hole population models that predict subsolar mass binaries.
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