Biology subjects

Simon, C. M.

Publications and source records attributed to Simon, C. M..

7 recordsLinked to original sources

bioRxiv2026

Incomplete cerebellar circuit restoration limits functional recovery following SMN therapy in severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is caused by a deficiency in the survival motor neuron (SMN) protein, resulting in degeneration of spinal motor neurons (MNs). However, persistent neurological deficits despite postnatal SMN-restoring therapies suggest that recovery of sensorimotor and supraspinal circuits may be incomplete. The cerebellum has recently emerged as a supraspinal contributor to motor deficits in the severe SMN{Delta}7 mouse model, yet it remains unclear whether cerebellar pathology is a conserved and therapeutically reversible feature across severe SMA mouse models and clinical subtypes. Here, we identify cerebellar pathology in Taiwanese SMA mice, characterized by hypoplasia, disrupted organization and loss of Purkinje cells (PCs), altered synaptic circuitry, and impaired cerebellar cortical output. Unlike the previously described p53-dependent PC degeneration in SMN{Delta}7 mice, cerebellar pathology in Taiwanese SMA mice was associated with developmental disorganization and external granule layer (EGL)-restricted p53 activation. Human cerebellar tissue mirrored this distinction, with p53 activation found in PCs from SMA Type I and in the EGL from SMA Type 0 individuals, indicating that cerebellar pathology arises through distinct mechanisms across severe forms of SMA. Importantly, two SMN-restoring strategies produced divergent therapeutic outcomes. In SMN{Delta}7 mice, AAV9-SMN prevented PC degeneration yet incompletely restored cerebellar circuitry. AAV9-SMN-treated Taiwanese mice developed severe ataxia-like deficits, retained profound cerebellar pathology, and survived to approximately one month of age. In contrast, systemic risdiplam rescued cerebellar pathology, motor behavior, and survival in both models. Together, these findings identify cerebellar pathology as a conserved yet distinct feature across severe forms of SMA and reveal cell type-specific tropism as a critical determinant of therapeutic outcome. More broadly, these findings suggest that successful recovery requires restoration of distributed supraspinal circuit integrity in addition to rescue of spinal motor pathways.

neuroscience↗

bioRxiv2026

A p53-ΔNp73 signaling axis drives selective motor neuron degeneration in spinal muscular atrophy

Selective neuronal vulnerability is a hallmark of many neurodegenerative diseases, yet how ubiquitous genetic insults cause highly selective neuronal loss remains poorly understood. In spinal muscular atrophy (SMA), reduced SMN levels trigger degeneration of specific motor neuron pools. Although non-apoptotic, p53-mediated death pathways have been implicated, p53 is expressed in both vulnerable and resistant neurons, leaving the downstream determinants of selective vulnerability unresolved. Here, we identify a p53-{Delta}Np73 signaling axis as a previously unrecognized execution pathway driving motor neuron degeneration. Using differential transcriptional profiling of SMA motor neurons following pharmacological modulation of p53 activity, we uncover p73 as a critical downstream mediator of neuronal death. Notably, SMN deficiency induces cell-autonomous, p53-dependent expression of the {Delta}Np73 isoform selectively in vulnerable, but not resistant, motor neurons. {Delta}Np73 induction precisely parallels the spatial and temporal pattern of degeneration in mouse models and is also detected in motor neurons from SMA patients. Strikingly, despite its established role as a pro-survival antagonist of p53, depletion of {Delta}Np73 improves motor neuron survival and partially preserves neuromuscular junction integrity in SMA mice. These findings reveal a context-dependent, isoform-specific functional switch in p53 family signaling that redirects a canonical survival factor into a driver of neurodegeneration, identifying a novel molecular mechanism underlying selective neuronal vulnerability in SMA and a potential therapeutic target for neuroprotection.

neuroscience↗

bioRxiv2026

A standardized framework resolves ambiguity in motor neuron loss across neurodegenerative diseases

Motor neuron (MN) loss is a hallmark of neurodegenerative disorders, yet its assessment remains variable, confounding mechanistic and therapeutic interpretation. To address this, we conducted a systematic review and meta-analysis of spinal muscular atrophy (SMA) mouse studies, revealing 60% variability in reported MN loss, largely attributable to nonspecific spinal cord sampling. Using a whole-segment approach with tissue clearing, MN tracing, and multimodal imaging, we confirmed segment-dependent differences in MN counts. Common MN markers (SMI-32, Nissl) lacked specificity, whereas choline acetyltransferase (ChAT) provided robust labeling in murine and human spinal cords. Deep learning-based whole-mount segmentation enabled unbiased MN quantification and validated manual counts. Integrating analysis with computational modeling established segment sampling as a key driver of variability and revealed degeneration patterns: widespread MN loss in amyotrophic lateral sclerosis (ALS), selective MN loss in severe SMA, and preservation in mild SMA models. These findings establish a framework for reproducible MN quantification. HighlightsO_LISpinal cord segment-specific analysis reduces variability and allows accurate MN quantification C_LIO_LIChAT is the most reliable MN marker in murine and human spinal cords C_LIO_LIDeep learning-based segmentation enables unbiased MN quantification in intact spinal cords C_LIO_LIMN degeneration is widespread in ALS but restricted to pools innervating proximal muscles in severe SMA C_LI

neuroscience↗

bioRxiv2024

HIF2α-dependent inhibition of mitochondrial clustering of glutaminase suppresses clear cell renal cell carcinoma

Clear cell renal cell carcinomas (ccRCC) are largely driven by HIF2 and are avid consumers of glutamine. However, inhibitors of glutaminase1 (GLS1), the first step in glutaminolysis, have not shown benefit in phase III trials, and HIF2 inhibition, recently FDA-approved for treatment of ccRCC, shows great but incomplete benefits, underscoring the need to better understand the roles of glutamine and HIF2 in ccRCC. Here, we report that glutamine deprivation rapidly redistributes GLS1 into isolated clusters within mitochondria across diverse cell types, but not in ccRCC. GLS1 clustering is rapid (1-3 hours) and reversible, is specifically driven by reduced intracellular glutamate, and is mediated by mitochondrial fission. Clustered GLS1 markedly enhances glutaminase activity and promotes cell death under glutamine-deprived conditions. HIF2 prevents GLS1 clustering, independently of its transcriptional activity, thereby protecting ccRCC cells from cell death induced by glutamine deprivation. Reversing this protection, by genetic expression of GLS1 mutants that constitutively cluster, enhances ccRCC cell death in culture and suppresses ccRCC growth in vivo. These findings provide multiple insights into cellular glutamine handling, including a novel metabolic pathway by which HIF2 promotes ccRCC, and reveals a potential therapeutic avenue to synergize with HIF2 inhibition in the treatment of ccRCC.

cancer biology↗

bioRxiv2023

Peripherally derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo

One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 (LGI1-mAbs), derived from patient circulating B cells. These were directed towards both major domains of LGI1, LRR (n=5) and EPTP (n=5) and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied using electrophysiology and immunostaining. By comparison to control-mAb injected rats (n=6), video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events (245{+/-}83 vs. 7.8{+/-}7.8 in controls; p=0.002). Memory was not impaired in the novel object recognition test. Local field potential recordings from postmortem brain slices showed spontaneous ictal-like spike activity in the CA3 region (p=0.03). The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield (6 controls; 7 LGI1-mAbs; p=0.01) Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.

neuroscience↗

bioRxiv2021

SMN controls neuromuscular junction integrity through U7 snRNP

The neuromuscular junction (NMJ) is an essential synapse for animal survival whose loss is a key hallmark of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). While insights into the function of the causative genes implicate RNA dysregulation in NMJ pathogenesis, the RNA-mediated mechanisms controlling the biology of this specialized synapse that go awry in disease remain elusive. Here, we show that activity of the SMA-determining SMN protein in the assembly of U7 small nuclear ribonucleoprotein (snRNP), which functions in the 3-end processing of replication-dependent histone mRNAs, is required for NMJ integrity. AAV9-mediated gene delivery of U7-specific Lsm10 and Lsm11 proteins selectively enhances U7 snRNP assembly, corrects histone mRNA processing defects, and rescues key structural and functional abnormalities of neuromuscular pathology in SMA mice - including NMJ denervation, reduced synaptic transmission, and skeletal muscle atrophy. Furthermore, U7 snRNP dysfunction induced by SMN deficiency drives selective loss of the synaptic organizing protein Agrin at NMJs innervating vulnerable axial muscles of SMA mice, revealing an unanticipated link between U7-dependent histone mRNA processing and motor neuron-derived expression of an essential factor for NMJ biology. Together, these findings establish a direct contribution of U7 snRNP dysfunction to the neuromuscular phenotype in SMA and the requirement of RNA-mediated histone gene regulation for maintaining functional synaptic connections between motor neurons and muscles.

neuroscience↗

bioRxiv2019

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

Reduced expression of the SMN protein causes spinal muscular atrophy (SMA) - an inherited neurodegenerative disease characterized by multiple synaptic deficits and motor neuron loss. Here, we show that AAV9-mediated delivery of Stasimon - a gene encoding an ER-resident transmembrane protein regulated by SMN - improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons of SMA mice, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In SMA motor neurons, Stasimon suppresses the neurodegenerative process by selectively reducing phosphorylation but not upregulation of the tumor suppressor p53, both of which are converging events required to trigger neuronal death. We further show that Stasimon deficiency synergizes with SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of cellular pathways that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.

neuroscience↗