The VPS35-D620N mutation is associated with Parkinson's disease and can be a target for gene therapy

There is evidence that the VPS35 protein impacts degradation of dopaminergic (DA) neuron lifespan and that the D620N mutation is associated with a kind of Parkinson's disease (PD) mimicking idiopathic PD. The incidence of this mutation and the likely pathogenic effects of additional VPS35 variants is unclear. Other unusual VPS35 mutations may put people at risk for Parkinson's disease, but the level of risk has yet to be determined.Due to the functional and genetic links between VPS35 and other PD-associated genes, rare VPS35 variants may be a key extra component in developing the PD phenotype in people with other mutations with inadequate penetration. Genetic association analysis could remedy this issue in the near future.VPS35-associated PD neuropathology is another significant aspect. Since just one D620N mutant carrier has been studied at autopsy to date, limited information is available about the neuropathological spectrum of PD patients with VPS35 mutations. It is yet unknown if neuronal loss in VPS35-related PD occurs just in SNc or affects other brain areas such as locus coeruleus, cortex, hippocampus and other structures. Neuropathology of VPS35-D620N mice models demonstrated severe tau pathology and axonal degradation, but no evidence of SYN inclusions. It's uncertain if PD individuals with VPS35 mutations have the same features.More study on the role of VPS35 in enhancing DA neuron survival is also needed to better understand the metabolic pathways damaged by VPS35 mutations and identify new therapy goals. The D620N VPS35 KI model, paired with the parkinQ311X mouse model, is one of the first monogenic PD models to recapitulate the fundamental PD feature: DA neuronal breakdown in SNc. These mouse models can be used to identify and assess drug targets. Because the neurodegenerative molecular pathways in many types of Parkinson's disease are so similar, drugs that confer neuroprotection in VPS35 models could be studied in other, more common types of Parkinson's disease.

Impact of Exercise on Immunometabolism in Multiple Sclerosis

Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

Ngly1 −/− rats develop neurodegenerative phenotypes and pathological abnormalities in their peripheral and central nervous systems

N-glycanase 1 (NGLY1) deficiency, an autosomal recessive disease caused by mutations in the NGLY1 gene, is characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, movement disorders and other neurological phenotypes. Because of few animal models that recapitulate these clinical signatures, the mechanisms of the onset of the disease and its progression are poorly understood, and the development of therapies is hindered. In this study, we generated the systemic Ngly1-deficient rodent model, Ngly1−/− rats, which showed developmental delay, movement disorder, somatosensory impairment and scoliosis. These phenotypes in Ngly1−/− rats are consistent with symptoms in human patients. In accordance with the pivotal role played by NGLY1 in endoplasmic reticulum-associated degradation processes, cleaving N-glycans from misfolded glycoproteins in the cytosol before they can be degraded by the proteasome, loss of Ngly1 led to accumulation of cytoplasmic ubiquitinated proteins, a marker of misfolded proteins in the neurons of the central nervous system of Ngly1−/− rats. Histological analysis identified prominent pathological abnormalities, including necrotic lesions, mineralization, intra- and extracellular eosinophilic bodies, astrogliosis, microgliosis and significant loss of mature neurons in the thalamic lateral and the medial parts of the ventral posterior nucleus and ventral lateral nucleus of Ngly1−/− rats. Axonal degradation in the sciatic nerves was also observed, as in human subjects. Ngly1−/− rats, which mimic the symptoms of human patients, will be a useful animal model for preclinical testing of therapeutic options and understanding the detailed mechanisms of NGLY1 deficiency.

Climbing-inspired twining electrodes using shape memory for peripheral nerve stimulation and recording

Peripheral neuromodulation has been widely used throughout clinical practices and basic neuroscience research. However, the mechanical and geometrical mismatches at current electrode-nerve interfaces and complicated surgical implantation often induce irreversible neural damage, such as axonal degradation. Here, compatible with traditional 2D planar processing, we propose a 3D twining electrode by integrating stretchable mesh serpentine wires onto a flexible shape memory substrate, which has permanent shape reconfigurability (from 2D to 3D), distinct elastic modulus controllability (from ~100 MPa to ~300 kPa), and shape memory recoverability at body temperature. Similar to the climbing process of twining plants, the temporarily flattened 2D stiff twining electrode can naturally self-climb onto nerves driven by 37°C normal saline and form 3D flexible neural interfaces with minimal constraint on the deforming nerves. In vivo animal experiments, including right vagus nerve stimulation for reducing the heart rate and action potential recording of the sciatic nerve, demonstrate the potential clinical utility.

Perinodal glial swelling mitigates axonal degradation in a model of axonal injury

Mild traumatic brain injury (mTBI) has been associated with the damage to myelinated axons in white matter tracts. Animal models and in vitro studies suggest that axonal degradation develops during a latent period following a traumatic event. This delay has been attributed to slowly developing axonal membrane depolarization that is initiated by injury-induced ionic imbalance and in turn, leads to the activation of Ca2+ proteases via pathological accumulation of Ca2+. However, the mechanisms mitigating the transition to axonal degradation after injury remain elusive. We addressed this question in a detailed biophysical model of axonal injury that incorporated ion exchange and glial swelling mechanisms. We show that glial swelling, which often co-occurs with mTBI, promotes axonal survival by regulating extracellular K+ dynamics, extending the range of injury parameters in which axons exhibit stable membrane potential postinjury. In addition, glial swelling was instrumental in reducing axonal sensitivity to repetitive stretch injury that occurred several minutes following the first one. Results of this study suggest that acute post-traumatic swelling of perinodal astrocytes helps prevent or postpone axonal degradation by maintaining physiologically relevant levels of extracellular K+.

ATP Release through Lysosomal Exocytosis from Peripheral Nerves: The Effect of Lysosomal Exocytosis on Peripheral Nerve Degeneration and Regeneration after Nerve Injury

Studies have shown that lysosomal activation increases in Schwann cells after nerve injury. Lysosomal activation is thought to promote the engulfment of myelin debris or fragments of injured axons in Schwann cells during Wallerian degeneration. However, a recent interpretation of lysosomal activation proposes a different view of the phenomenon. During Wallerian degeneration, lysosomes become secretory vesicles and are activated for lysosomal exocytosis. The lysosomal exocytosis triggers adenosine 5′-triphosphate (ATP) release from peripheral neurons and Schwann cells during Wallerian degeneration. Exocytosis is involved in demyelination and axonal degradation, which facilitate nerve regeneration following nerve degeneration. At this time, released ATP may affect the communication between cells in peripheral nerves. In this review, our description of the relationship between lysosomal exocytosis and Wallerian degeneration has implications for the understanding of peripheral nerve degenerative diseases and peripheral neuropathies, such as Charcot-Marie-Tooth disease or Guillain-Barré syndrome.

Arachidonic Acid Derivatives and Their Role in Peripheral Nerve Degeneration and Regeneration

After peripheral nerve injury, a process of axonal degradation, debris clearance, and subsequent regeneration is initiated by complex local signaling, called Wallerian degeneration (WD). This process is in part mediated by neuroglia as well as infiltrating inflammatory cells and regulated by inflammatory mediators such as cytokines, chemokines, and the activation of transcription factors also related to the inflammatory response. Part of this neuroimmune signaling is mediated by the innate immune system, including arachidonic acid (AA) derivatives such as prostaglandins and leukotrienes. The enzymes responsible for their production, cyclooxygenases and lipooxygenases, also participate in nerve degeneration and regeneration. The interactions between signals for nerve regeneration and neuroinflammation go all the way down to the molecular level. In this paper, we discuss the role that AA derivatives might play during WD and nerve regeneration, and the therapeutic possibilities that arise.