Reducing synuclein accumulation improves neuronal survival after spinal cord injury

Abstract

Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells. We report here that spinal cord injury caused a select subset of giant reticulospinal neurons to accumulate synuclein, a synaptic vesicle-associated protein best known for its atypical aggregation and causal role in neurodegeneration in Parkinson’s and other diseases. Post-injury synuclein accumulation took the form of punctate aggregates throughout the somata and occurred selectively in dying neurons, but not in those that survived. In contrast, another synaptic vesicle protein, synaptotagmin, did not accumulate in response to injury. We further show that the post-injury synuclein accumulation was greatly attenuated after single dose application of either the “molecular tweezer” inhibitor, CLR01, or a translation-blocking synuclein morpholino. Consequently, reduction of synuclein accumulation not only improved neuronal survival, but also increased the number of axons in the spinal cord proximal and distal to the lesion. This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury.

Inhibition of Mutant αB Crystallin‐Induced Protein Aggregation by a Molecular Tweezer

“…CLR01 suppressed α‐synuclein fibril assembly and disaggregated preformed fibrils in neurons, rescuing the animal's neurodegenerative phenotype and promoting survival in zebrafish embryos expressing human α‐synuclein or treated with the Parkinson disease–linked pesticide Ziram . Similarly, it reduced α‐synuclein accumulation and aggregation and promoted neuron survival in a lamprey model of spinal‐cord injury . CLR01 also was able to inhibit Aβ fibrillogenesis and cleared existing Aβ and tau aggregates in the brain of an Alzheimer disease model in mice .…”

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

“…39 CLR01 treatment reduced synuclein accumulation by 34% in the “poor survivor” neurons. The reduction in synuclein accumulation correlated with an increase from 8% to 37% survival of these neurons.…”

GABA promotes survival and axonal regeneration in identifiable descending neurons after spinal cord injury in larval lampreys

“…But, even in lampreys not all descending neurons of the brain are able to regenerate their axons through the site of injury after a complete spinal cord transection (Davis and McClellan, 1994;Jacobs et al, 1997, Armstrong et al, 2003Cornide-Petronio et al, 2011;Busch and Morgan, 2012). The lamprey brainstem contains approximately 30 large individually identifiable descending reticulospinal neurons that vary greatly in their ability for axonal regeneration after SCI, even when their axons run in similar paths in a spinal cord that is permissive for axonal regrowth (Jacobs et al, 1997;Busch and Morgan, 2012;Fogerson et al, 2016). Some identifiable descending neurons of lampreys are considered "good regenerators" (i.e.…”