Synaptogenic gene therapy with FGF22 improves circuit plasticity and functional recovery following spinal cord injury

Functional recovery following incomplete spinal cord injury (SCI) depends on the rewiring of motor circuits during which supraspinal connections form new contacts onto spinal relay neurons. We have recently identified a critical role of the presynaptic organizer FGF22 for the formation of new synapses in the remodeling spinal cord. Here, we now explore whether and how targeted overexpression of FGF22 can be used to mitigate the severe functional consequences of SCI. By targeting FGF22 expression to either long propriospinal neurons, excitatory interneurons, or a broader population of interneurons, we establish that FGF22 can enhance neuronal rewiring both in a circuit‐specific and comprehensive way. We can further demonstrate that the latter approach can restore functional recovery when applied either on the day of the lesion or within 24 h. Our study thus establishes viral gene transfer of FGF22 as a new synaptogenic treatment for SCI and defines a critical therapeutic window for its application

Second harmonic imaging of axonal microtubules and examining the impact of their molecular conformation on mitochondrial transport

Mitochondria are often referred to as the power plants of the cell as they provide energy to ensure healthy cell functioning. These organelles are created in the soma and are transported to different cell compartments with high energy needs via the cell's cytoskeleton. Two of the major components of the cytoskeleton involved in mitochondrial transport are the microtubule and actin network. While most cell types have no spatial constriction for mitochondria to move around, nerve cells pose a specific risk for efficient transport as these cells can have processes that are up to 1 meter long. Generally a neuron has one single axon which sends out information towards other cells and a highly branched dendritic network, receiving information from other cells. Apart from the length of these projections, the axon is extremely narrow with an average diameter of 1 μm. As mitochondria are rather large organelles, the passage through this narrow shaft could easily get obstructed. Therefore we propose that tight regulation of mitochondrial fission events and the organisation of the cytoskeleton, specifically of the microtubule and actin network, is required to facilitate mitochondrial transport within this constricted space. Advanced imaging techniques will be used in combination with optogenetic tools to assess fission events and the organisation of the cytoskeleton during mitochondrial transport in axons.status: publishe

Nano-positioning and tubulin conformation contribute to axonal transport regulation of mitochondria along microtubules

Correct spatiotemporal distribution of organelles and vesicles is crucial for healthy cell functioning and is regulated by intracellular transport mechanisms. Controlled transport of bulky mitochondria is especially important in polarized cells such as neurons that rely on these organelles to locally produce energy and buffer calcium. Mitochondrial transport requires and depends on microtubules that fill much of the available axonal space. How mitochondrial transport is affected by their position within the microtubule bundles is not known. Here, we found that anterograde transport, driven by kinesin motors, is susceptible to the molecular conformation of tubulin in neurons both in vitro and in vivo. Anterograde velocities negatively correlate with the density of elongated tubulin dimers like guanosine triphosphate (GTP)-tubulin. The impact of the tubulin conformation depends primarily on where a mitochondrion is positioned, either within or at the rim of microtubule bundle. Increasing elongated tubulin levels lowers the number of motile anterograde mitochondria within the microtubule bundle and increases anterograde transport speed at the microtubule bundle rim. We demonstrate that the increased kinesin velocity and density on microtubules consisting of elongated dimers add to the increased mitochondrial dynamics. Our work indicates that the molecular conformation of tubulin contributes to the regulation of mitochondrial motility and as such to the local distribution of mitochondria along axons

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis.

International audienceWe recently reported an association of the SPP1 rs9138 and rs11439060 functional variants with the risk of rheumatoid arthritis (RA), the association being greater in anti-citrullinated protein autoantibody (ACPA)-negative patients. We hypothesised that SPP1 may contribute to the severity of joint destruction in RA, specifically in the ACPA-negative population.Patients with RA in the ESPOIR cohort underwent genotyping for SPP1 rs9138 and rs11439060. Radiographs of the hands and feet were obtained at the first visit and at 1- and 2-year follow-up. Association analyses were performed by ACPA status. A replication study of the relevant subset of the Leiden Early Arthritis Clinic (EAC) cohort was performed.In the ESPOIR cohort (652 patients), rs9138 was significantly associated with radiological progression of joint destruction at 2 years, the association being restricted to 358 ACPA-negative patients (p=0.034). In the replication study with the Leiden EAC cohort (273 ACPA-negative patients), rs4754, which is in complete linkage disequilibrium with rs9138, was significantly associated with joint damage progression in ACPA-negative patients at 2- and 7-year follow-up (p=0.019 and p=0.005, respectively). Combined analysis of the two cohorts revealed a 0.95-fold rate of joint destruction per year per minor allele (p=0.022).The SPP1 rs9138 variant contributes to joint damage progression in ACPA-negative RA

Synaptogenic gene therapy with FGF22 improves circuit plasticity and functional recovery following spinal cord injury

Abstract Functional recovery following incomplete spinal cord injury (SCI) depends on the rewiring of motor circuits during which supraspinal connections form new contacts onto spinal relay neurons. We have recently identified a critical role of the presynaptic organizer FGF22 for the formation of new synapses in the remodeling spinal cord. Here, we now explore whether and how targeted overexpression of FGF22 can be used to mitigate the severe functional consequences of SCI. By targeting FGF22 expression to either long propriospinal neurons, excitatory interneurons, or a broader population of interneurons, we establish that FGF22 can enhance neuronal rewiring both in a circuit‐specific and comprehensive way. We can further demonstrate that the latter approach can restore functional recovery when applied either on the day of the lesion or within 24 h. Our study thus establishes viral gene transfer of FGF22 as a new synaptogenic treatment for SCI and defines a critical therapeutic window for its application

Coordinated supraspinal and spinal neurostimulation guides circuit rewiring and unlocks motor recovery after spinal cord injury (RNASeq Data)

 A comparison of differentially expressed genes in the cervical 3rd and 4th segments of mouse spinal cord following spinal cord injury and coordinated stimulation of corticospinal projection neurons and long propriospinal neurons.</p