Upper motor neurons are a target for gene therapy and UCHL1 is necessary and sufficient to improve cellular integrity of diseased upper motor neurons

Abstract

There are no effective cures for upper motor neuron (UMN) diseases, such as amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and hereditary spastic paraplegia. Here, we show UMN loss occurs independent of spinal motor neuron degeneration and that UMNs are indeed effective cellular targets for gene therapy, which offers a potential solution especially for UMN disease patients. UCHL1 (ubiquitin C-terminal hydrolase-L1) is a deubiquitinating enzyme crucial for maintaining free ubiquitin levels. Corticospinal motor neurons (CSMN, a.k.a UMNs in mice) show early, selective, and profound degeneration in Uchl1 nm3419 (UCHL1 −/− ) mice, which lack all UCHL1 function. When UCHL1 activity is ablated only from spinal motor neurons, CSMN remained intact. However, restoring UCHL1 specifically in CSMN of UCHL1 −/− mice via directed gene delivery, was sufficient to improve CSMN integrity to the healthy control levels. In addition, when UCHL1 gene was delivered selectively to CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology via AAV-mediated retrograde transduction, the disease causing misfolded SOD1 and mutant human TDP-43 were reduced in hSOD1 G93A and prpTDP-43 A315T models, respectively. Diseased CSMN retained their neuronal integrity and cytoarchitectural stability in two different mouse models that represent two distinct causes of neurodegeneration in ALS.

SBT-272 improves TDP-43 pathology in the ALS motor cortex by modulating mitochondrial integrity, motility, and function

“…UMNs are clinically important neurons that are in part responsible for the initiation and modulation of voluntary movement, which is impaired in ALS patients. Despite the prevailing die-back hypothesis, (Clark et al, 2016; Dadon-Nachum et al, 2011), there is now ample evidence showing UMN degeneration is an early event in ALS (Geevasinga et al, 2015; Pradhan and Bellingham, 2021; Vucic and Kiernan, 2006) and that UMN degeneration may neither be a function of spinal motor neurons loss nor depend on spinal motor neuron degeneration (Genc et al, 2022b). Improvement of UMNs health should have a direct impact on motor neuron circuitry, and potentially the health of spinal motor neurons, as well as the integrity of neuromuscular junctions (Thomsen et al, 2014), highlighting the necessity of improving UMN health, in addition to spinal motor neurons, as a treatment strategy.…”

“…However, there is now ample evidence showing the relevance of improving UMN health as a potential treatment strategy. UMN degeneration occurs early in the disease (Geevasinga et al, 2015; Geevasinga et al, 2016; Thomsen et al, 2014), and is not necessarily be a function of spinal motor neuron degeneration (Eisen, 2021; Genc et al, 2022b; Marques et al, 2021). The generation and characterization of a novel UMN reporter line, in which UMNs can be distinguished among other cortical cells by an eGFP expression that is stable and long-lasting (Yasvoina et al, 2013), now enables cell-type specific analysis of UMNs with cellular precision that was not possible before.…”

Biological networks and complexity in early-onset motor neuron diseases

“…Using this systems network approach, ubiquitin-C was identified as a common therapeutic target between the various genetic forms of ALS and ALS-FTD (31). Gene delivery of UCHL1-a key enzyme controlling the amount of ubiquitin-C present in polyubiquitin chains on proteins-to upper motor neurons improves motor neuron phenotype in multiple models of ALS (60). Future studies will demonstrate the therapeutic potential of UCHL1 modulation in multiple early-onset MNDs as well as identify via network analysis additional common targets for therapeutic benefit.…”