Experimental Evidence that Disease Pathogenesis in Sporadic ALS is Unique and Distinct from that seen in Familial ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron death. The majority of ALS cases are sporadic ALS (sALS) patients with no known genetic mutations. Only 5-10% of ALS patients have familial ALS (fALS) associated with an identified genetic mutation. Approximately 15-20% of fALS patients carry a mutation in the superoxide dismutase 1 (SOD1) gene. Although sALS and fALS patients present similar clinical symptoms, it is unknown whether the mechanisms underlying disease pathogenesis are the same. We aimed to address this question by assessing the effects of intrathecal delivery of cerebrospinal fluid (CSF) obtained from sALS and SOD1 patients into mice.

8-10 week old female mice underwent laminectomies at cervical levels 4 and 5, and 3μl of either sALS or SOD1 CSF was injected under the dura mater into the subarachnoid space. Control mice received either saline, CSF from healthy individuals, or CSF from other neurological diseases (OND). Forelimb motor deficits were assessed at 1 day post injection, then mice were perfused for histological analyses of the spinal cord. All motor testing and histological analyses were performed blinded. On motor testing, sALS CSF-injected mice exhibited significantly impaired forelimb function compared to controls and SOD1 CSF-injected mice, which were unimpaired. Pathologically, motor neuron death was observed in spinal cords of sALS CSF-injected mice, as determined by a significantly lower number of ChAT-positive motor neurons and increased activated-caspase3 staining. This was not observed in SOD1 CSF-injected mice. Nonphosphorylated neurofilament-H (SMI-32) expression was also significantly elevated in the grey matter surrounding motor neurons in sALS CSF-injected mice. Evidence of reactive astrogliosis and microglial activation was observed in spinal cords of sALS CSF-injected mice, as revealed by stronger expression of GFAP and amoeboid microglial morphology, respectively. Glutamate transporter-1 expression appeared higher in the ventral horns of sALS CSF-injected mice, suggesting that glutamate excitotoxicity may be involved in inducing functional deficits and pathology. Overall, these findings suggest that disease mechanisms in sALS are distinct from those occurring in fALS.