Genetic ablation ofSOD1^G37Rselectively from corticofugal projection neurons protects corticospinal neurons from degeneration without affecting ALS onset and progression

Abstract

While clinical evidence of combined degeneration of the bulbar and spinal motor neurons (MN) together with the corticospinal neurons (CSN) is required to diagnose Amyotrophic Lateral Sclerosis (ALS), preclinical studies have mostly concentrated on MN, leaving aside the CSN and their contribution to ALS onset and progression. Recent studies carried on ALS patients suggest that the disease may initiate in the motor cortex and spread to its projection targets, along the corticofugal axonal projections (including CSN), either via altered neuronal excitability and subsequent excitotoxicity, or via prion-like propagation of misfolded proteins. We recently provided first experimental arguments in favour of the corticofugal hypothesis of ALS, demonstrating that CSN and other subcerebral projection neurons were toxic in a context of ALS. Here, we aimed to determine how CSN may be detrimental to their downstream targets, and what governs their degeneration. To answer these questions, we took advantage of the FloxedSOD1 G37R mouse model of ALS that allows genetic ablation of the mutant transgene in selected cells upon Cre-mediated recombination, and crossed it to the CrymCreER T2 mouse line that we purposely designed to genetically target CSN and other corticofugal projection neurons (CFuPN) populations. We demonstrate that excision of the mutant SOD1 G37R transgene from the CSN is sufficient to prevent their death, suggesting that CSN degeneration mostly relies on cellintrinsic mechanisms. However, genetic ablation of SOD1 G37R transgene from the corticofugal neurons had no effect on disease onset and survival. The data thus indicate that the toxicity of CFuPN in the context of ALS, and corticofugal propagation of the disease, are not mediated by the presence of misfolded mutant proteins, but more likely by other aspects of the cortical pathology, possibly hyperexcitability.

Absence of Subcerebral Projection Neurons Is Beneficial in a Mouse Model of Amyotrophic Lateral Sclerosis

“…In a recent study, we genetically ablated the SOD1 G37R transgene from corticofugal projection neurons. This was sufficient to prevent CSN degeneration in a cell‐autonomous manner but had no impact on disease onset and survival, ruling out a major contribution of misfolded protein propagation from the corticofugal neurons to their targets on disease occurrence and progression in this mouse model 40 . On the contrary, knock‐down of the SOD1 G93A mutant transgene in the posterior motor cortex of a rat model of ALS using AAV9 delayed disease onset and extended survival 36 .…”