Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy.

Despite intense research into the multifaceted etiology of neurodegenerative diseases (ND), they remain incurable. Here we provide a brief overview of several major ND and explore novel therapeutic approaches. Although the cause (s) of ND are not fully understood, the accumulation of misfolded/aggregated proteins in the brain is a common pathological feature. This aggregation may initiate disruption of Ca++ signaling, which is an early pathological event leading to altered dendritic structure, neuronal dysfunction, and cell death. Presently, ND gene therapies remain unidimensional, elusive, and limited to modifying one pathological feature while ignoring others. Considering the complexity of signaling cascades in ND, we discuss emerging therapeutic concepts and suggest that deciphering the molecular mechanisms involved in dendritic pathology may broaden the phenotypic spectrum of ND treatment. An innovative multiplexed gene transfer strategy that employs silencing and/or over-expressing multiple effectors could preserve vulnerable neurons before they are lost. Such therapeutic approaches may extend brain health span and ameliorate burdensome chronic disease states.

Intellectual disability: dendritic anomalies and emerging genetic perspectives.

Intellectual disability (ID) corresponds to several neurodevelopmental disorders of heterogeneous origin in which cognitive deficits are commonly associated with abnormalities of dendrites and dendritic spines. These histological changes in the brain serve as a proxy for underlying deficits in neuronal network connectivity, mostly a result of genetic factors. Historically, chromosomal abnormalities have been reported by conventional karyotyping, targeted fluorescence in situ hybridization (FISH), and chromosomal microarray analysis. More recently, cytogenomic mapping, whole-exome sequencing, and bioinformatic mining have led to the identification of novel candidate genes, including genes involved in neuritogenesis, dendrite maintenance, and synaptic plasticity. Greater understanding of the roles of these putative ID genes and their functional interactions might boost investigations into determining the plausible link between cellular and behavioral alterations as well as the mechanisms contributing to the cognitive impairment observed in ID. Genetic data combined with histological abnormalities, clinical presentation, and transgenic animal models provide support for the primacy of dysregulation in dendrite structure and function as the basis for the cognitive deficits observed in ID. In this review, we highlight the importance of dendrite pathophysiology in the etiologies of four prototypical ID syndromes, namely Down Syndrome (DS), Rett Syndrome (RTT), Digeorge Syndrome (DGS) and Fragile X Syndrome (FXS). Clinical characteristics of ID have also been reported in individuals with deletions in the long arm of chromosome 10 (the q26.2/q26.3), a region containing the gene for the collapsin response mediator protein 3 (CRMP3), also known as dihydropyrimidinase-related protein-4 (DRP-4, DPYSL4), which is involved in dendritogenesis. Following a discussion of clinical and genetic findings in these syndromes and their preclinical animal models, we lionize CRMP3/DPYSL4 as a novel candidate gene for ID that may be ripe for therapeutic intervention.

Collapsin Response Mediator Proteins: Novel Targets for Alzheimer's Disease.

Numerous experimental and postmortem studies have increasingly reported dystrophic axons and dendrites, and alterations of dendritic spine morphology and density in the hippocampus as prominent changes in the early stages of Alzheimer's disease (AD). Furthermore, these alterations tend to correlate well with the progressive cognitive decline observed in AD. For these reasons, and because these neurite structures have a capacity to re-grow, re-establish lost connections, and are critical for learning and memory, there is compelling evidence to suggest that therapeutic interventions aimed at preventing their degradation or promoting their regrowth may hold tremendous promise in preventing the progression of AD. In this regard, collapsin response mediator proteins (CRMPs), a family of phosphoproteins playing a major role in axon guidance and dendritic growth, are especially interesting. The roles these proteins play in neurons and immune cells are reviewed here.

Opposing Morphogenetic Defects on Dendrites and Mossy Fibers of Dentate Granular Neurons in CRMP3-Deficient Mice.

Collapsin response mediator proteins (CRMPs) are highly expressed in the brain during early postnatal development and continue to be present in specific regions into adulthood, especially in areas with extensive neuronal plasticity including the hippocampus. They are found in the axons and dendrites of neurons wherein they contribute to specific signaling mechanisms involved in the regulation of axonal and dendritic development/maintenance. We previously identified CRMP3's role on the morphology of hippocampal CA1 pyramidal dendrites and hippocampus-dependent functions. Our focus here was to further analyze its role in the dentate gyrus where it is highly expressed during development and in adults. On the basis of our new findings, it appears that CRMP3 has critical roles both in axonal and dendritic morphogenesis of dentate granular neurons. In CRMP3-deficient mice, the dendrites become dystrophic while the infrapyramidal bundle of the mossy fiber shows aberrant extension into the stratum oriens of CA3. This axonal misguided projection of granular neurons suggests that the mossy fiber-CA3 synaptic transmission, important for the evoked propagation of the activity of the hippocampal trisynaptic circuitry, may be altered, whereas the dystrophic dendrites may impair the dynamic interactions with the entorhinal cortex, both expected to affect hippocampal function.

Xanthones from the twigs of Garcinia oblongifolia and their antidiabetic activity.

Three new xanthones, oblongixanthone F-H (1-3), along with eight known xanthones (4-11), were isolated from an EtOAc extract of the twigs of Garcinia oblongifolia. Their structures were elucidated by spectroscopic analysis including 1D- and 2D-NMR spectroscopy and mass spectrometry. The antidiabetic effects of all isolated compounds were evaluated by in vitro α-glucosidase and PTP1B inhibition assays. Compound 11 was the most active compound, and inhibited α-glucosidase and PTP1B with IC50 values of 1.7±0.5 and 14.1±3.5µM, respectively.

Neuronal networks in mental diseases and neuropathic pain: Beyond brain derived neurotrophic factor and collapsin response mediator proteins.

The brain is a complex network system that has the capacity to support emotion, thought, action, learning and memory, and is characterized by constant activity, constant structural remodeling, and constant attempt to compensate for this remodeling. The basic insight that emerges from complex network organization is that substantively different networks can share common key organizational principles. Moreover, the interdependence of network organization and behavior has been successfully demonstrated for several specific tasks. From this viewpoint, increasing experimental/clinical observations suggest that mental disorders are neural network disorders. On one hand, single psychiatric disorders arise from multiple, multifactorial molecular and cellular structural/functional alterations spreading throughout local/global circuits leading to multifaceted and heterogeneous clinical symptoms. On the other hand, various mental diseases may share functional deficits across the same neural circuit as reflected in the overlap of symptoms throughout clinical diagnoses. An integrated framework including experimental measures and clinical observations will be necessary to formulate a coherent and comprehensive understanding of how neural connectivity mediates and constraints the phenotypic expression of psychiatric disorders.

Mapping CRMP3 domains involved in dendrite morphogenesis and voltage-gated calcium channel regulation.

Although hippocampal neurons are well-distinguished by the morphological characteristics of their dendrites and their structural plasticity, the mechanisms involved in regulating their neurite initiation, dendrite growth, network formation and remodeling are still largely unknown, in part because the key molecules involved remain elusive. Identifying new dendrite-active cues could uncover unknown molecular mechanisms that would add significant understanding to the field and possibly lead to the development of novel neuroprotective therapy because these neurons are impaired in many neuropsychiatric disorders. In our previous studies, we deleted the gene encoding CRMP3 in mice and identified the protein as a new endogenous signaling molecule that shapes diverse features of the hippocampal pyramidal dendrites without affecting axon morphology. We also found that CRMP3 protects dendrites against dystrophy induced by prion peptide PrP(106-126). Here, we report that CRMP3 has a profound influence on neurite initiation and dendrite growth of hippocampal neurons in vitro. Our deletional mapping revealed that the C-terminus of CRMP3 probably harbors its dendritogenic capacity and supports an active transport mechanism. By contrast, overexpression of the C-terminal truncated CRMP3 phenocopied the effect of CRMP3 gene deletion with inhibition of neurite initiation or decrease in dendrite complexity, depending on the stage of cell development. In addition, this mutant inhibited the activity of CRMP3, in a similar manner to siRNA. Voltage-gated calcium channel inhibitors prevented CRMP3-induced dendritic growth and somatic Ca(2+) influx in CRMP3-overexpressing neurons was augmented largely via L-type channels. These results support a link between CRMP3-mediated Ca(2+) influx and CRMP3-mediated dendritic growth in hippocampal neurons.

CRMP3 is required for hippocampal CA1 dendritic organization and plasticity.

In vitro studies have pointed to the collapsin response mediator proteins (CRMPs) as key regulators of neurite outgrowth and axonal differentiation. CRMP3 is expressed mostly in the nervous system during development but remains at high levels in the hippocampus of adults. To explore CRMP3 function in vivo, we generated mice with targeted disruption of the CRMP3 gene. Immunohistochemistry and Golgi staining of CA1 showed abnormal dendrite and spine morphogenesis in the hippocampus of CRMP3-deficient mice. Apical dendrites displayed an increase in undulation and a reduction in length and branching points. Basal dendrites also exhibited a reduction in length with an alteration in soma stem distribution and an increased number of thick dendrites localized in stratum oriens (SO). Long-term potentiation (LTP) was impaired in this area. These data indicate an important role for CRMP3 in dendrite arborization, guide-posts navigation, and neuronal plasticity.