A missense mutation in human INSC causes peripheral neuropathy.

PAR3/INSC/LGN form an evolutionarily conserved complex required for asymmetric cell division in the developing brain, but its post-developmental function and disease relevance in the peripheral nervous system (PNS) remains unknown. We mapped a new locus for axonal Charcot-Marie-Tooth disease (CMT2) and identified a missense mutation c.209 T > G (p.Met70Arg) in the INSC gene. Modeling the INSCM70R variant in Drosophila, we showed that it caused proprioceptive defects in adult flies, leading to gait defects resembling those in CMT2 patients. Cellularly, PAR3/INSC/LGN dysfunction caused tubulin aggregation and necrotic neurodegeneration, with microtubule-stabilizing agents rescuing both morphological and functional defects of the INSCM70R mutation in the PNS. Our findings underscore the critical role of the PAR3/INSC/LGN machinery in the adult PNS and highlight a potential therapeutic target for INSC-associated CMT2.

The pathophysiological role of dihydroceramide desaturase in the nervous system.

Dihydroceramide desaturase 1 (DEGS1) converts dihydroceramide (dhCer) to ceramide (Cer) by inserting a C4-C5 trans (∆4E) double bond into the sphingoid backbone. Low DEGS activity causes accumulation of dhCer and other dihydrosphingolipid species. Although dhCer and Cer are structurally very similar, their imbalances can have major consequences both in vitro and in vivo. Mutations in the human DEGS1 gene are known to cause severe neurological defects, such as hypomyelinating leukodystrophy. Likewise, inhibition of DEGS1 activity in fly and zebrafish models causes dhCer accumulation and subsequent neuronal dysfunction, suggesting that DEGS1 activity plays a conserved and critical role in the nervous system. Dihydrosphingolipids and their desaturated counterparts are known to control various essential processes, including autophagy, exosome biogenesis, ER stress, cell proliferation, and cell death. Furthermore, model membranes with either dihydrosphingolipids or sphingolipids exhibit different biophysical properties, including membrane permeability and packing, thermal stability, and lipid diffusion. However, the links between molecular properties, in vivo functional data, and clinical manifestations that underlie impaired DEGS1 function remain largely unresolved. In this review, we summarize the known biological and pathophysiological roles of dhCer and its derivative dihydrosphingolipid species in the nervous system, and we highlight several possible disease mechanisms that warrant further investigation.

Drosophila as a model to study autophagy in neurodegenerative diseases and digestive tract.

Autophagy regulates cellular homeostasis by degrading and recycling cytosolic components and damaged organelles. Disruption of autophagic flux has been shown to induce or facilitate neurodegeneration and accumulation of autophagic vesicles is overt in neurodegenerative diseases. The fruit fly Drosophila has been used as a model system to identify new factors that regulate physiology and disease. Here we provide a historical perspective of how the fly models have offered mechanistic evidence to understand the role of autophagy in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth neuropathy, and polyglutamine disorders. Autophagy also plays a pivotal role in maintaining tissue homeostasis and protecting organism health. The gastrointestinal tract regulates organism health by modulating food intake, energy balance, and immunity. Growing evidence is strengthening the link between autophagy and digestive tract health in recent years. Here, we also discuss how the fly models have advanced the understanding of digestive physiology regulated by autophagy.

Conveyance of cortical pacing for parkinsonian tremor-like hyperkinetic behavior by subthalamic dysrhythmia.

Parkinson's disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.