Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of gait disorders. Their pathological hallmark is a length-dependent distal axonopathy of nerve fibers in the corticospinal tract. Involvement of other neurons can cause additional neurological symptoms, which define a diverse set of complex hereditary spastic paraplegias. We present two siblings who have the unusual combination of early-onset spastic paraplegia, optic atrophy, and neuropathy. Genome-wide SNP-typing, linkage analysis, and exome sequencing revealed a homozygous c.316C>T (p.R106C) variant in the Trk-fused gene (TFG) as the only plausible mutation. Biochemical characterization of the mutant protein demonstrated a defect in its ability to self-assemble into an oligomeric complex, which is critical for normal TFG function. In cell lines, TFG inhibition slows protein secretion from the endoplasmic reticulum (ER) and alters ER morphology, disrupting organization of peripheral ER tubules and causing collapse of the ER network onto the underlying microtubule cytoskeleton. The present study provides a unique link between altered ER architecture and neurodegeneration.membrane trafficking | COPII-mediated secretion | ER exit site H ereditary spastic paraplegias (HSPs) are a diverse group of disorders characterized by spastic weakness in the lower extremities, which results from degeneration of upper motoneuron axons in the corticospinal tract (1, 2). Based on the presence or absence of other neurological abnormalities, HSPs are classified as complicated or pure, respectively. In addition to lower-limb spasticity, complicated forms of HSP may be associated with ataxia, mental retardation, dementia, extrapyramidal signs, visual dysfunction, and/or epilepsy. HSPs are typically progressive, but age of onset is highly variable. The heterogeneity in clinical presentation is accompanied by genetic heterogeneity. To date, more than 40 different genetic loci, which include nearly all modes of inheritance, have been linked to HSPs (1-5). However, in nearly half of these cases, the identities of the causative genes remain unknown. The identification of additional HSP genes and, more importantly, the functional characterization of their encoded products, will both contribute to our understanding of the pathomechanisms underlying HSPs and reveal the general requirements for lifelong axonal maintenance.More than half the HSP cases in North America and Northern Europe can be attributed to defects in organelle dynamics (6). In particular, mutations that impact the architecture of the endoplasmic reticulum (ER) are common in patients with HSP. The ER is comprised of a network of membrane tubules and sheetlike cisternae that extend throughout the cytoplasm and encase the nucleus (7-9). Several factors contribute to this architecture, including (i) membrane-bending proteins of the REEP and reticulon families; (ii) regulators of the microtubule cytoskeleton, which governs the spatial patterning of the ER network; and (iii) components of the ear...

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Synaptotagmin-1 regulates synaptic vesicle fusion, but little is known about the remaining syt isoforms. Syt-pHluorin reporters are used to show that only two syts are on synaptic vesicles, whereas other isoforms are selectively targeted to dendrites, axons, or both axons and dendrites, where they undergo exocytosis and endocytosis with distinct kinetics.

Recent reports suggest that botulinum neurotoxin (BoNT) A, which is widely used clinically to inhibit neurotransmission, can spread within networks of neurons to have distal effects, but this remains controversial. Moreover, it is not known whether other members of this toxin family are transferred between neurons. Here, we investigate the potential distal effects of BoNT/A, D, and tetanus toxin, using central neurons grown in microfluidic devices. Toxins acted upon the neurons that mediated initial entry, but all three toxins were also taken-up via an alternative pathway, into non-acidified organelles that mediated retrograde transport to the somato-dendritic compartment. Toxins were then released into the media where they entered, and exerted their effects upon, upstream neurons. These findings directly demonstrate that these agents undergo transcytosis and interneuronal transfer in an active form, resulting in long distance effects.