Whole‐blood dysregulation of actin‐cytoskeleton pathway in adult spinal muscular atrophy patients

Abstract

Objective: Recent advances in therapeutics have improved prognosis for severely affected spinal muscular atrophy (SMA) type 1 and 2 patients, while the best method of treatment for SMA type 3 patients with later onset of disease is unknown. To better characterize the SMA type 3 population and provide potential therapeutic targets, we aimed to understand gene expression differences in whole blood of SMA type 3 patients (n = 31) and age-and gendermatched controls (n = 34). Methods: We performed the first large-scale whole blood transcriptomic screen with L1000, a rapid, high-throughput gene expression profiling technology that uses 978 landmark genes to capture a representation of the transcriptome and predict expression of 9196 additional genes. Results: The primary downregulated KEGG pathway in adult SMA type 3 patients was "Regulation of Actin Cytoskeleton," and downregulated expression of key genes in this pathway, including ROCK1, RHOA, and ACTB, was confirmed in the same whole blood samples using RT-qPCR. SMA type 3 patientderived fibroblasts had lower expression of these genes compared to control fibroblasts from unaffected first-degree relatives. Overexpression of SMN levels using an AAV vector in fibroblasts did not normalize ROCK1, RHOA, and ACTB mRNA expression, indicating the involvement of additional genes in cytoskeleton dynamic regulation. Interpretation: Our findings from whole blood and patient-derived fibroblasts suggest SMA type 3 patients have decreased expression of actin cytoskeleton regulators. These observations provide new insights and potential therapeutic targets for SMA patients with longstanding denervation and secondary musculoskeletal pathophysiology.

Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy

“…Of note, a recent paper by Siranosian et al. described changes in the actin cytoskeleton regulation pathway in whole blood transcriptome of adult SMA patients, confirming the systemic nature of pathway dysregulation in SMA ( 38 ). Combining μCT with these results, we present evidence suggesting that SMN depletion leads to a range of morphological and molecular developmental perturbations in SMA, manifesting in advance of the onset of degenerative neuromuscular symptoms commonly associated with the disease.…”

Molecular Biomarkers for the Diagnosis, Prognosis, and Pharmacodynamics of Spinal Muscular Atrophy

“…Whole transcriptome. In a study that conducted a whole blood transcriptomic screen, seven downregulated and three upregulated KEGG pathways were observed, with the most significantly downregulated pathway being "Regulation of Actin Cytoskeleton" [53]. A study that analyzed the transcriptome from fibroblasts using the Gene Expression Plate "Neurodegeneration" observed a decrease in the expression of SMN1, SNCA, SV2A, and SYN2 mRNA in SMA patients compared to HCs [54].…”

Increased systemic HSP70B levels in spinal muscular atrophy infants

“… 6 , 7 , 8 To further identify novel systemic biomarkers to predict and track SMA severity across a range of phenotypes, all newly diagnosed SMA patients, their siblings, and their families are offered enrollment in the SPOT SMA Longitudinal Pediatric Data Repository (LPDR) database and linked biorepository. 9 , 10 , 11 The SPOT SMA LPDR was launched in 2016 to extend the Project Cure SMA LPDR, with appropriate modifications for anticipatory follow‐up for SMA newborns and affected and unaffected siblings (NCT02831296). Here, we performed RNA sequencing and differential expressions analyses in samples from SMA type 1 subjects under 1 year old and age‐matched healthy control subjects to identify novel SMA biomarkers early in life.…”

“…Cerebrospinal fluid and plasma/serum neurofilament (NF) levels are the markers of neuronal damage and have been recently identified as a potential prognostic and treatment responsive biomarker in SMA and other neurodegenerative diseases 6‐8 . To further identify novel systemic biomarkers to predict and track SMA severity across a range of phenotypes, all newly diagnosed SMA patients, their siblings, and their families are offered enrollment in the SPOT SMA Longitudinal Pediatric Data Repository (LPDR) database and linked biorepository 9‐11 . The SPOT SMA LPDR was launched in 2016 to extend the Project Cure SMA LPDR, with appropriate modifications for anticipatory follow‐up for SMA newborns and affected and unaffected siblings (NCT02831296).…”