Selective Vulnerability of Neuronal Subtypes in ALS: A Fertile Ground for the Identification of Therapeutic Targets

It is well defined that subpopulations of motoneurons have different vulnerability to the pathology causing amyotrophic lateral sclerosis (ALS). In the spinal cord, the fast fatigable motoneurons have been shown to be the first to degenerate, followed by fatigue-resistant and slow motoneurons. In contrast motoneurons located in the Onuf’s and oculomotor nuclei appear to be resistant to disease. With a focus on research mainly done on mice overexpressing the mutated human superoxide dismutase (SOD1) protein, we review recent studies exploring the mechanisms that underlie the selective vulnerability of the various motoneuron subtypes. By comparing differences in gene expression between these populations, it has been possible to identify factors, which critically determine the survival of motoneurons and the neuromuscular function in the pathologic context of ALS. Furthermore, we discuss the contribution of non-cell autonomous processes, involving glial cells and the skeletal muscle, in the neurodegenerative process. Exploring the cause of neurodegeneration from the angle of the selective neuronal vulnerability has recently led to the identification of novel targets, which open opportunities for therapeutic intervention against ALS

Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation

Missense mutations and extra copies of the α-Synuclein gene result in Parkinson disease (PD). Human stem and progenitor cells can be expanded from embryonic tissues and provide a source of non-transformed neural cells to explore the effects of these pathogenic mutations specifically in human nervous tissue. We over-expressed the wild type, A53T and A30P forms of α-synuclein in expanded populations of progenitors derived from the human fetal cortex. The protein localized in the nucleus and around microvesicles. Only the A53T form was acutely toxic, suggesting a unique vulnerability of these progenitors to this mutation. Interestingly, constitutive over-expression of wild-type α-synuclein progressively impaired the innate ability of progenitors to switch toward gliogenesis at later passages. To explore the effect of α-synuclein on neuronal subtypes selectively affected in PD, such as dopaminergic neurons, α-synuclein and its mutations were also over-expressed in terminally differentiating neuroectodermal cultures derived from human embryonic stem cells (hESC). Alpha-synuclein induced acute cytotoxicity and reduced the number of neurons expressing either tyrosine hydroxylase or gamma-aminobutyric acid over time. Consistent with the selective vulnerability of ventral midbrain dopaminergic neurons, α-synuclein cytotoxicity appeared most pronounced following FGF8/SHH specification and was decreased by inhibition of dopamine synthesis. Together, these data show that α-synuclein over-expressed in human neural embryonic cells results in patterns of degeneration that in some cases match features of Parkinson Disease. Thus, neural cells derived from hESC provide a useful model system to understand the development of α-synuclein-related pathologies and allow therapeutic drug screenin

The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain

The deposition of amyloid-beta (Aβ) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Aβ is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by γ-secretase, an intramembrane-cleaving protease with multiple substrates, including the Notch receptors. Endogenous modulation of γ-secretase is pointed to be implicated in the sporadic, age-dependent form of AD. Moreover, specifically modulating Aβ production has become a priority for the safe treatment of AD because the inhibition of γ-secretase results in adverse effects that are related to impaired Notch cleavage. Here, we report the identification of the adipocyte differentiation protein APMAP as a novel endogenous suppressor of Aβ generation. We found that APMAP interacts physically with γ-secretase and its substrate APP. In cells, the partial depletion of APMAP drastically increased the levels of APP-CTFs, as well as uniquely affecting their stability, with the consequence being increased secretion of Aβ. In wild-type and APP/ presenilin 1 transgenic mice, partial adeno-associated virus-mediated APMAP knockdown in the hippocampus increased Aβ production by ∼20 and ∼55%, respectively. Together, our data demonstrate that APMAP is a negative regulator of Aβ production through its interaction with APP and γ-secretase. All observed APMAP phenotypes can be explained by an impaired degradation of APP-CTFs, likely caused by an altered substrate transport capacity to the lysosomal/autophagic syste

FOXO3 determines the accumulation of α-synuclein and controls the fate of dopaminergic neurons in the substantia nigra

Parkinson's disease (PD) is characterized by the selective degeneration of neuronal populations presumably due to pathogenic interactions between aging and predisposing factors such as increased levels of α-synuclein. Here, we genetically modulate the activity of the transcription factor Forkhead box protein O3 (FOXO3) in adult nigral dopaminergic neurons using viral vectors and explore how this determinant of longevity impacts on neuronal fate in normal and diseased conditions. We find that dopaminergic neurons are particularly vulnerable to changes in FOXO3 activity in the substantia nigra. While constitutive activation has proapoptotic effects leading to neuronal loss, inhibition of FOXO-mediated transcription by a dominant-negative competitor causes oxidative damage and is detrimental at high vector dose. To address the role of FOXO3 in PD, we modulate its activity in dopaminergic neurons overexpressing human α-synuclein. In this pathogenic condition, we find that FOXO inhibition has protective effects, suggesting that this transcription factor ultimately contributes to neuronal cell death. Nevertheless, mild FOXO3 activity also protects nigral neurons against the accumulation of human α-synuclein, albeit to a lesser extent. FOXO3 reduces the amount of α-synuclein present in the soluble protein fraction and promotes the coalescence of dense proteinase K-resistant aggregates, with an accumulation of autophagic vacuoles containing lipofuscin. Consistent with these in vivo observations, we find that FOXO3 controls autophagic flux in neuronal cells. Altogether, these results point to FOXO3 as an important determinant of neuronal survival in the substantia nigra, which may oppose α-synuclein accumulation and proteotoxicit

The spine of the swan: A Herschel study of the DR21 ridge and filaments in Cygnus X

In order to characterise the cloud structures responsible for the formation of high-mass stars, we present Herschel observations of the DR21 environment. Maps of the column density and dust temperature unveil the structure of the DR21 ridge and several connected filaments. The ridge has column densities larger than 1e23/cm^2 over a region of 2.3 pc^2. It shows substructured column density profiles and branching into two major filaments in the north. The masses in the studied filaments range between 130 and 1400 Msun whereas the mass in the ridge is 15000 Msun. The accretion of these filaments onto the DR21 ridge, suggested by a previous molecular line study, could provide a continuous mass inflow to the ridge. In contrast to the striations seen in e.g., the Taurus region, these filaments are gravitationally unstable and form cores and protostars. These cores formed in the filaments potentially fall into the ridge. Both inflow and collisions of cores could be important to drive the observed high-mass star formation. The evolutionary gradient of star formation running from DR21 in the south to the northern branching is traced by decreasing dust temperature. This evolution and the ridge structure can be explained by two main filamentary components of the ridge that merged first in the south.Comment: 8 pages, 5 figures, accepted for publication as a Letter in Astronomy and Astrophysic

The <i>Herschel</i> view of the massive star-forming region NGC 6334

Aims: Fundamental to any theory of high-mass star formation are gravity and turbulence. Their relative importance, which probably changes during cloud evolution, is not known. By investigating the spatial and density structure of the high-mass star-forming complex NGC 6334 we aim to disentangle the contributions of turbulence and gravity. Methods: We used Herschel PACS and SPIRE imaging observations from the HOBYS key programme at wavelengths of 160, 250, 350, and 500 μm to construct dust temperature and column density maps. Using probability distribution functions (PDFs) of the column density determined for the whole complex and for four distinct sub-regions (distinguished on the basis of differences in the column density, temperature, and radiation field), we characterize the density structure of the complex. We investigate the spatial structure using the Δ-variance, which probes the relative amount of structure on different size scales and traces possible energy injection mechanisms into the molecular cloud. Results: The Δ-variance analysis suggests that the significant scales of a few parsec that were found are caused by energy injection due to expanding HII regions, which are numerous, and by the lengths of filaments seen everywhere in the complex. The column density PDFs have a lognormal shape at low densities and a clearly defined power law at high densities for all sub-regions whose slope is linked to the exponent α of an equivalent spherical density distribution. In particular with α = 2.37, the central sub-region is largly dominated by gravity, caused by individual collapsing dense cores and global collapse of a larger region. The collapse is faster than free-fall (which would lead only to α = 2) and thus requires a more dynamic scenario (external compression, flows). The column density PDFs suggest that the different sub-regions are at different evolutionary stages, especially the central sub-region, which seems to be in a more evolved stage

Alpha-synuclein ferrireductase activity is detectible in vivo, is altered in Parkinson's disease and increases the neurotoxicity of DOPAL

© 2017 Elsevier Inc. The normal cellular role of α-synuclein is of potential importance in understanding diseases in which an aggregated form of the protein has been implicated. A potential loss or change in the normal function of α-synuclein could play a role in the aetiology of diseases such as Parkinson's disease. Recently, it has been suggested that α-synuclein could cause the enzymatic reduction of iron and a cellular increase in Fe(II) levels. Experiments were carried out to determine if such activity could be measured in vivo. Experiments with rats overexpressing human α-synuclein in nigral dopaminergic neurons demonstrated a correlation between α-synuclein expression and ferrireductase activity. Furthermore, studies on tissue from Parkinson's disease patient brains showed a significant decrease in ferrireductase activity, possibly due to deposition of large amounts of inactive protein. Cellular studies suggest that increase ferrireductase activity results in increased levels of dopamine metabolites and increased sensitivity to the toxicity of DOPAL. These findings demonstrate that α-synuclein ferrireductase activity is present in vivo and its alteration may play a role in neuron loss in disease

The M16 molecular complex under the influence of NGC6611. Herschel's perspective of the heating effect on the Eagle Nebula

We present Herschel images from the HOBYS key program of the Eagle Nebula (M16) in the far-infrared and sub-millimetre, using the PACS and SPIRE cameras at 70{\mu}m, 160{\mu}m, 250{\mu}m, 350{\mu}m, 500{\mu}m. M16, home to the Pillars of Creation, is largely under the influence of the nearby NGC6611 high-mass star cluster. The Herschel images reveal a clear dust temperature gradient running away from the centre of the cavity carved by the OB cluster. We investigate the heating effect of NGC6611 on the entire M16 star-forming complex seen by Herschel including the diffuse cloud environment and the dense filamentary structures identified in this region. In addition, we interpret the three-dimensional geometry of M16 with respect to the nebula, its surrounding environment, and the NGC6611 cavity. The dust temperature and column density maps reveal a prominent eastern filament running north-south and away from the high-mass star-forming central region and the NGC6611 cluster, as well as a northern filament which extends around and away from the cluster. The dust temperature in each of these filaments decreases with increasing distance from the NGC6611 cluster, indicating a heating penetration depth of \sim 10 pc in each direction in 3 - 6 \times 10^{22} cm-2 column density filaments. We show that in high-mass star-forming regions OB clusters impact the temperature of future star-forming sites, modifying the initial conditions for collapse and effecting the evolutionary criteria of protostars developed from spectral energy distributions. Possible scenarios for the origin of the morphology seen in this region are discussed, including a western equivalent to the eastern filament, which was destroyed by the creation of the OB cluster and its subsequent winds and radiation.Comment: 12 pages, including 3 appendix, 9 figures, accepted by A&

Polo-like kinase 2 regulates selective autophagic α-synuclein clearance and suppresses its toxicity in vivo

An increase in α-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering α-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances α-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of α-synuclein requires both phosphorylation at S129 and PLK2/α-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human α-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by α-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and α-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of α-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies