The role of aging and brain-derived neurotrophic factor signaling in expression of base excision repair genes in the human brain.

DNA damage is a central contributor to the aging process. In the brain, a major threat to the DNA is the considerable amount of reactive oxygen species produced, which can inflict oxidative DNA damage. This type of damage is removed by the base excision repair (BER) pathway, an essential DNA repair mechanism, which contributes to genome stability in the brain.

Dimerization of the Alzheimer's disease pathogenic receptor SORLA regulates its association with retromer.

, the gene encoding the large multidomain SORLA protein, has emerged as only the fourth gene that when mutated can by itself cause Alzheimer's disease (AD), and as a gene reliably linked to both the early- and late-onset forms of the disease. SORLA is known to interact with the endosomal trafficking regulatory complex called retromer in regulating the recycling of endosomal cargo, including the amyloid precursor protein (APP) and the glutamate receptor GluA1. Nevertheless, SORLA's precise structural-functional relationship in endosomal recycling tubules remains unknown.

Comparative transcriptional analysis of satellite glial cell injury response.

Satellite glial cells (SGCs) tightly surround and support primary sensory neurons in the peripheral nervous system and are increasingly recognized for their involvement in the development of neuropathic pain following nerve injury. SGCs are difficult to investigate due to their flattened shape and tight physical connection to neurons and their rapid changes in phenotype and protein expression when cultured . Consequently, several aspects of SGC function under normal conditions as well as after a nerve injury remain to be explored.

Sortilin Modulates Schwann Cell Signaling and Remak Bundle Regeneration Following Nerve Injury.

Peripheral nerve regeneration relies on the ability of Schwann cells to support the regrowth of damaged axons. Schwann cells re-differentiate when reestablishing contact with the sprouting axons, with large fibers becoming remyelinated and small nociceptive fibers ensheathed and collected into Remak bundles. We have previously described how the receptor sortilin facilitates neurotrophin signaling in peripheral neurons regulated trafficking of Trk receptors.

Correction to: Prodromal neuroinvasion of pathological α-synuclein in brainstem reticular nuclei and white matter lesions in a model of α-synucleinopathy.

[This corrects the article DOI: 10.1093/braincomms/fcab104.].

Recombinant adeno-associated virus mediated gene delivery in the extracranial nervous system of adult mice by direct nerve immersion.

This protocol outlines a minimally invasive and quickly performed approach for transgene delivery in the extracranial nervous system of adult mice using recombinant adeno-associated virus (AAV). The technique, named Sciatic Nerve Direct Immersion (SciNDi), relies on the direct bilateral immersion of the exposed sciatic nerve with AAV. We show that in comparison with intramuscular AAV delivery, SciNDi results in widespread transduction in connected neuroanatomical tracts both in the sciatic nerve trunk and the lumbar spinal cord.

Discrepancy in the Usage of GFAP as a Marker of Satellite Glial Cell Reactivity.

Satellite glial cells (SGCs) surrounding the neuronal somas in peripheral sensory ganglia are sensitive to neuronal stressors, which induce their reactive state. It is believed that such induced gliosis affects the signaling properties of the primary sensory neurons and is an important component of the neuropathic phenotype leading to pain and other sensory disturbances. Efforts to understand and manipulate such gliosis relies on reliable markers to confirm induced SGC reactivity and ultimately the efficacy of targeted intervention.

The Prion-Like Spreading of Alpha-Synuclein in Parkinson's Disease: Update on Models and Hypotheses.

The pathological aggregation of the presynaptic protein α-synuclein (α-syn) and propagation through synaptically coupled neuroanatomical tracts is increasingly thought to underlie the pathophysiological progression of Parkinson's disease (PD) and related synucleinopathies. Although the precise molecular mechanisms responsible for the spreading of pathological α-syn accumulation in the CNS are not fully understood, growing evidence suggests that de novo α-syn misfolding and/or neuronal internalization of aggregated α-syn facilitates conformational templating of endogenous α-syn monomers in a mechanism reminiscent of prions. A refined understanding of the biochemical and cellular factors mediating the pathological neuron-to-neuron propagation of misfolded α-syn will potentially elucidate the etiology of PD and unravel novel targets for therapeutic intervention.

Prodromal neuroinvasion of pathological α-synuclein in brainstem reticular nuclei and white matter lesions in a model of α-synucleinopathy.

Neuropathological observations in neurodegenerative synucleinopathies, including Parkinson disease, implicate a pathological role of α-synuclein accumulation in extranigral sites during the prodromal phase of the disease. In a transgenic mouse model of peripheral-to-central neuroinvasion and propagation of α-synuclein pathology (via hindlimb intramuscular inoculation with exogenous fibrillar α-synuclein: the M83 line, expressing the mutant human Ala53Thr α-synuclein), we studied the development and early-stage progression of α-synuclein pathology in the CNS of non-symptomatic (i.e.

α-Synuclein pathology in Parkinson disease activates homeostatic NRF2 anti-oxidant response.

Circumstantial evidence points to a pathological role of alpha-synuclein (aSyn; gene symbol SNCA), conferred by aSyn misfolding and aggregation, in Parkinson disease (PD) and related synucleinopathies. Several findings in experimental models implicate perturbations in the tissue homeostatic mechanisms triggered by pathological aSyn accumulation, including impaired redox homeostasis, as significant contributors in the pathogenesis of PD. The nuclear factor erythroid 2-related factor (NRF2/Nrf2) is recognized as 'the master regulator of cellular anti-oxidant response', both under physiological as well as in pathological conditions.

Expression of an alternatively spliced variant of SORL1 in neuronal dendrites is decreased in patients with Alzheimer's disease.

SORL1 is strongly associated with both sporadic and familial forms of Alzheimer's disease (AD), but a lack of information about alternatively spliced transcripts currently limits our understanding of the role of SORL1 in AD. Here, we describe a SORL1 transcript (SORL1-38b) characterized by inclusion of a novel exon (E38b) that encodes a truncated protein. We identified E38b-containing transcripts in several brain regions, with the highest expression in the cerebellum and showed that SORL1-38b is largely located in neuronal dendrites, which is in contrast to the somatic distribution of transcripts encoding the full-length SORLA protein (SORL1-fl).

Trans-synaptic spreading of alpha-synuclein pathology through sensory afferents leads to sensory nerve degeneration and neuropathic pain.

Pain is a common non-motor symptom of Parkinson's disease (PD), with current limited knowledge of its pathophysiology. Here, we show that peripheral inoculation of mouse alpha-synuclein (α-Syn) pre-formed fibrils, in a transgenic mouse model of PD, elicited retrograde trans-synaptic spreading of α-Syn pathology (pSer129) across sensory neurons and dorsal nerve roots, reaching central pain processing regions, including the spinal dorsal horn and the projections of the anterolateral system in the central nervous system (CNS). Pathological peripheral to CNS propagation of α-Syn aggregates along interconnected neuronal populations within sensory afferents, was concomitant with impaired nociceptive response, reflected by mechanical allodynia, reduced nerve conduction velocities (sensory and motor) and degeneration of small- and medium-sized myelinated fibers.

Modulation of Small RNA Signatures in Schwann-Cell-Derived Extracellular Vesicles by the p75 Neurotrophin Receptor and Sortilin.

Schwann cells (SCs) are the main glial cells of the peripheral nervous system (PNS) and are known to be involved in various pathophysiological processes, such as diabetic neuropathy and nerve regeneration, through neurotrophin signaling. Such glial trophic support to axons, as well as neuronal survival/death signaling, has previously been linked to the p75 neurotrophin receptor (p75) and its co-receptor Sortilin. Recently, SC-derived extracellular vesicles (EVs) were shown to be important for axon growth and nerve regeneration, but cargo of these glial cell-derived EVs has not yet been well-characterized.

Schwann cell p75 neurotrophin receptor modulates small fiber degeneration in diabetic neuropathy.

Diabetic neuropathy has an incidence as high as 50% of diabetic patients and is characterized by damage to neurons, Schwann cells and blood vessels within the peripheral nervous system. The low-affinity neurotrophin receptor p75 (p75 ), particularly expressed by the Schwann cells in the peripheral nerve, has previously been reported to play a role in developmental myelination and cell survival/death. Increased levels of p75 , in the endoneurium and plasma from diabetic patients and rodent models of disease, have been observed, proposing that this receptor might be involved in the pathogenesis of diabetic neuropathy.

SORLA Expression in Synaptic Plexiform Layers of Mouse Retina.

Sorting protein-related receptor containing LDLR class A repeats (SORLA; also known as LR11) exerts intraneuronal trafficking functions in the central nervous system. Recently, involvement of SORLA in retinogenesis was proposed, but no studies have examined yet in detail the expression pattern of this sorting receptor in the retina. Here, we provide a spatio-temporal characterization of SORL1 mRNA and its translational product SORLA in the postnatal mouse retina.

Gene Transfer in Rodent Nervous Tissue Following Hindlimb Intramuscular Delivery of Recombinant Adeno-Associated Virus Serotypes AAV2/6, AAV2/8, and AAV2/9.

Recombinant adeno-associated virus (rAAV) vectors have emerged as the safe vehicles of choice for long-term gene transfer in mammalian nervous system. Recombinant adeno-associated virus-mediated localized gene transfer in adult nervous system following direct inoculation, that is, intracerebral or intrathecal, is well documented. However, recombinant adeno-associated virus delivery in defined neuronal populations in adult animals using less-invasive methods as well as avoiding ectopic gene expression following systemic inoculation remain challenging.

A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain.

Maladaptive plasticity involving increased expression of AMPA-type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell-permeable, high-affinity (~2 nM) peptide inhibitor, Tat-P -(C5) , of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex.

Sortilin gates neurotensin and BDNF signaling to control peripheral neuropathic pain.

Neuropathic pain is a major incurable clinical problem resulting from peripheral nerve trauma or disease. A central mechanism is the reduced expression of the potassium chloride cotransporter 2 (KCC2) in dorsal horn neurons induced by brain-derived neurotrophic factor (BDNF), causing neuronal disinhibition within spinal nociceptive pathways. Here, we demonstrate how neurotensin receptor 2 (NTSR2) signaling impairs BDNF-induced spinal KCC2 down-regulation, showing how these two pathways converge to control the abnormal sensory response following peripheral nerve injury.

Peripheral Nerve Regeneration Is Independent From Schwann Cell p75 Expression.

Schwann cell reprogramming and differentiation are crucial prerequisites for neuronal regeneration and re-myelination to occur following injury to peripheral nerves. The neurotrophin receptor p75 has been identified as a positive modulator for Schwann cell myelination during development and implicated in promoting nerve regeneration after injury. However, most studies base this conclusion on results obtained from complete p75 knockout mouse models and cannot dissect the specific role of p75 expressed by Schwann cells.

Functional and Structural Changes of the Blood-Nerve-Barrier in Diabetic Neuropathy.

The incidence of diabetes mellitus is approaching global epidemic proportions and should be considered a major health-care problem of modern societies in the twenty-first century. Diabetic neuropathy is a common chronic complication of diabetes and, although an adequate glycemic control can reduce the frequency of diabetic neuropathy in type 1 diabetes, the majority of type 2 diabetic patients will develop this complication. The underlying cellular and molecular mechanisms are still poorly understood, preventing the development of effective treatment strategies.

An alternative transcript of the Alzheimer's disease risk gene SORL1 encodes a truncated receptor.

SORL1 encodes a 250-kDa protein named sorLA, a functional sorting receptor for the amyloid precursor protein (APP). Several single nucleotide polymorphisms of the gene SORL1, encoding sorLA, are genetically associated with Alzheimer's disease (AD). In the existing literature, SORL1 is insufficiently described at the transcriptional level, and there is very limited amount of functional data defining different transcripts.

Peripheral Glial Cells in the Development of Diabetic Neuropathy.

The global prevalence of diabetes is rapidly increasing, affecting more than half a billion individuals within the next few years. As diabetes negatively affects several physiological systems, this dramatic increase represents not only impaired quality of life on the individual level but also a huge socioeconomic challenge. One of the physiological consequences affecting up to half of diabetic patients is the progressive deterioration of the peripheral nervous system, resulting in spontaneous pain and eventually loss of sensory function, motor weakness, and organ dysfunctions.