Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. Here, we report that reduced SMN protein level alters miRNA expression and distribution in neurons. In particular, miR-183 levels are increased in neurites of SMN-deficient neurons. We demonstrate that miR-183 regulates translation of mTor via direct binding to its 3' UTR. Interestingly, local axonal translation of mTor is reduced in SMN-deficient neurons, and this can be recovered by miR-183 inhibition. Finally, inhibition of miR-183 expression in the spinal cord of an SMA mouse model prolongs survival and improves motor function of Smn-mutant mice. Together, these observations suggest that axonal miRNAs and the mTOR pathway are previously unidentified molecular mechanisms contributing to SMA pathology.

Expansion microscopy1,2 is an increasingly widespread technology for nanoimaging, because its precise physical magnification of biological specimens enables ordinary microscopes to achieve nanoscale effective resolutions. Fluorescent labels such as antibodies can be applied either before or after expansion, with the latter offering the potential for better access to proteins within densely packed environments3–7. We here assess this possibility of epitope decrowding through physical expansion of proteins away from each other, using a 20x expansion protocol that we call expansion revealing (ExR), by labeling, within intact brain circuits, the same set of synaptic proteins both pre- and post-expansion. This comparison shows that post-expansion labeling introduces minimal spatial error and off-target staining relative to pre-expansion staining, while revealing the presence of proteins that are invisible when stained pre-expansion. Using ExR, we show in intact brain tissue the alignment of presynaptic calcium channels with postsynaptic machinery in nanocolumns, which may facilitate precision synaptic transmission, as well as the existence of periodic amyloid-containing nanoclusters containing ion channel proteins in Alzheimer’s model mice, which may help generate novel hypotheses for Alzheimer’s pathology and neural excitability. Thus, the decrowding power of ExR is able to reveal novel nanostructures within intact brain circuitry, and may find broad use in biology and medicine for unmasking nanostructures of importance in normal functions and disease.

No abstract

In mouse and human neurons, axonally secreted amyloid precursor protein (APP) fragments are processed in the cell body before being sorted into the axon in a process that requires endocytosis for the processing, but not axonal delivery, of APP.

Overexpression and/or abnormal cleavage of amyloid precursor protein (APP) are linked to Alzheimer's disease (AD) development and progression. However, the molecular mechanisms regulating cellular levels of APP or its processing, and the physiological and pathological consequences of altered processing are not well understood. Here, using mouse and human cells, we found that neuronal damage induced by UV irradiation leads to specific APP, APLP1, and APLP2 decline by accelerating their secretase-dependent processing. Pharmacological inhibition of endosomal/lysosomal activity partially protects UV-induced APP processing implying contribution of the endosomal and/or lysosomal compartments in this process. We found that a biological consequence of UV-induced ␥-secretase processing of APP is impairment of APP axonal transport. To probe the functional consequences of impaired APP axonal transport, we isolated and analyzed presumptive APP-containing axonal transport vesicles from mouse cortical synaptosomes using electron microscopy, biochemical, and mass spectrometry analyses. We identified a population of morphologically heterogeneous organelles that contains APP, the secretase machinery, molecular motors, and previously proposed and new residents of APP vesicles. These possible cargoes are enriched in proteins whose dysfunction could contribute to neuronal malfunction and diseases of the nervous system including AD. Together, these results suggest that damage-induced APP processing might impair APP axonal transport, which could result in failure of synaptic maintenance and neuronal dysfunction.

No abstract

With this issue of Neuron, we continue our series of special issues on neurological disease. This series highlights the efforts to understand the pathophysiology of disease, improve diagnosis, and ultimately alter clinical course. In the first installment of our series, we discussed various translational approaches to develop treatments for disorders of the nervous system. Understanding the mechanisms mediating disease is a crucial step toward finding cures, and in this issue, we present articles that evaluate the neural mechanisms underlying epilepsy, pain, neurodegeneration, and neurodevelopmental disorders. First, Jordan Stewart Farrell, Quynh-Anh Nguyen, and Ivan Soltesz review seizure mechanisms at the micro-and the macro-scale to advocate that both levels have to be examined and considered for a complete view of epilepsy and its effective treatment. In the previous special issue on translational approaches, Tracey et al. discussed the use of pain biomarkers for the effective treatment of pain. In the current issue, Ben Seymour illustrates that a reinforcement learning model of pain offers a mechanistic understanding of how the brain processes pain and supports its main function, which is the motivation to direct behavior away from harm. The next three articles discuss different aspects of the neural mechanisms underlying neurodegenerative diseases and their potential treatments. In his Perspective, Todd Golde explores the relationship between the immune system, brain proteinopathy, and neurodegenerative diseases. Golde argues that ''immunoproteostasis'' reflects multidirectional interactions between the immune system and the proteinopathies that are potential triggers of many neurodegenerative disorders. He then discusses the possibility of modulation of immunoproteostasis as a treatment option for neurodegenerative disease, particularly Alzheimer's. Matthew M. McGregor and Alexandra B. Nelson comprehensively review the circuit mechanisms of Parkinson's disease (PD). Specifically, the authors discuss the symptomatic and circuit aspects of many of the key clinical features of PD, including both motor and non-motor dysfunctions. In addition to the basal ganglia thalamocortical circuit central to PD, McGregor and Nelson also investigate PD-related changes in network activity. Next, Casey Cook and Leonard Petrucelli explore the cellular mechanisms underlying amyotrophic lateral sclerosis (ALS). Specifically, they focus on the pathogenic molecular consequences of repeat expansions in C9ORF72, which is the most common genetic cause of ALS, combined with the identification of new genetic mutations, to provide insight into the underlying mechanisms that cause ALS. As this article confirms, an accurate picture of the broad cell and molecular mechanisms underlying dysfunction is needed to develop a cure. Claudia Bagni and Suzanne Zukin review the synaptic mechanisms underlying two neurodevelopmental disorders, fragile X syndrome (FXS) and autism spectrum disorder (ASD). This broad article covers the aspects of FXS an...

In this issue of Neuron, we are proud to present the first in a series of special issues on neurological and neuropsychiatric disease. The three consecutively published issues will each center around a specific disease-related topic and feature a mixture of Reviews, Perspectives, and NeuroViews. Given the multifaceted nature of the disease field, we chose three themes to allow us to delve into the complexity and diversity of the selected areas. We narrowed the topics to translational approaches to neuroscience, mechanisms of disease, and advances in psychiatry. These topics exemplify the coordinated effort that is required to understand neural mechanisms at different levels to ultimately treat and cure disease. The articles discuss long-standing questions, recent advances, and future directions in this quickly developing sphere. Throughout the series, some diseases and approaches will be covered more than once, but in different contexts, reflecting the interdisciplinary nature of these endeavors In our first special issue, we focus on translational neuroscience, the process of applying insights from laboratory research to the development of clinical trials. It is a rapidly growing discipline in biomedical research and promises to expedite the discovery of new diagnostic tools and drug development as well as unconventional treatment strategies. This collection of pieces helps highlight the themes trending in preclinical to clinical work: gene therapy, advanced biomarkers, and new ways to approach disease research design. We believe that the issue will be of interest to a broad range of scientists, in both research and clinical practice. The first Perspective, by Irene Tracey, Clifford Woolf, and Nick Andrews, discusses pain biomarkers and their importance for the assessment and treatment of pathological pain. Given that pain is a qualitative sensory experience, the authors argue that quantifying pain via a variety of biomarkers is essential for an improved understanding of the disease. The next two Reviews focus on two progressive and devastating neurodegenerative diseases: Huntington disease (HD) and Alzheimer's disease (AD). In the first piece, clinician-scientists Sarah Tabrizi, Rhia Ghosh, and Blair Leavitt discuss the cutting edge of HD therapeutics. They review approaches to reduce mutant huntingtin protein by targeting huntingtin DNA, RNA, and the mutant protein itself, with the potential to ameliorate all its downstream pathogenic effects. It is an exciting time in this field, as clinical trials in patients are already underway. In their Review of AD, Micha€ el Belloy, Valerio Napolioni, and Michael Greicius explore ApoE4, a risk factor for AD, among other diseases. By focusing on human data, the authors discuss whether ApoE4 increases the risk for AD via a loss or gain of function. They argue that answering this question is crucial for the development of efficient gene-based therapies for AD. A comprehensive Review by Eloise Hudry and Luk Vandenberghe focuses on the utility of adeno-associated viral vecto...