New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise, Marc-Olivier; Kothary, Rashmi

doi:10.1002/acn3.423

Cited by 38 publications

(31 citation statements)

References 80 publications

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“…that is, we speculate that it may be related to possible effects on the immune system, similarly to previous reports for AAV8 vectors [42,43]. Seeing as SMA mice have an altered immune response [44,45] and that inflammation can display both protective and adverse systemic properties [46], including within the CNS [47] and muscle [48], it is possible that an activated immune response results in acute and/or intermittent benefits in AAV8-treated SMA animals. In summary, the limited impact of AAV8-Klf15 administration in SMA mice might be explained by several experimental conditions that most likely reduced our ability to increase Klf15 specifically in skeletal muscle at physiological levels and with the optimal timing, without influencing the function of other tissues and systems.…”

Section: Discussionsupporting

confidence: 81%

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

et al. 2020

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Spinal muscular atrophy (SMA) is a neuromuscular disease caused by loss of the survival motor neuron (SMN) gene. While there are currently two approved gene-based therapies for SMA, availability, high cost, and differences in patient response indicate that alternative treatment options are needed. Optimal therapeutic strategies will likely be a combination of SMN-dependent and-independent treatments aimed at alleviating symptoms in the central nervous system and peripheral muscles. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates key metabolic and ergogenic pathways in muscle. We have recently reported significant downregulation of Klf15 in muscle of presymptomatic SMA mice. Importantly, perinatal upregulation of Klf15 via transgenic and pharmacological methods resulted in improved disease phenotypes in SMA mice, including weight and survival. In the current study, we designed an adeno-associated virus serotype 8 (AAV8) vector to overexpress a codon-optimized Klf15 cDNA under the muscle-specific Spc5-12 promoter (AAV8-Klf15). Administration of AAV8-Klf15 to severe Taiwanese Smn −/− ; SMN2 or intermediate Smn 2B/− SMA mice significantly increased Klf15 expression in muscle. We also observed significant activity of the AAV8-Klf15 vector in liver and heart. AAV8-mediated Klf15 overexpression moderately improved survival in the Smn 2B/− model but not in the Taiwanese mice. An inability to specifically induce Klf15 expression at physiological levels in a time-and tissue-dependent manner may have contributed to this limited efficacy. Thus, our work demonstrates that an AAV8-Spc5-12 vector induces high gene expression as early as P2 in several tissues including muscle, heart, and liver, but highlights the challenges of achieving meaningful vector-mediated transgene expression of Klf15.

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Section: Discussionsupporting

confidence: 81%

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

et al. 2020

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“…Moreover, in addition to the MN loss, a remarkable neuroinflammation is reported in SMA (McGivern et al, 2013 ; Rindt et al, 2015 ; Deguise and Kothary, 2017 ): therefore, we evaluated astrogliosis in the spinal cord by the analysis of GFAP signal in the spinal ventral horns. Results showed that D-JNKI1 treatment in SMA reduced astrogliosis compared to SMA controls (SMA PBS, N = 6; SMA D-JNKI1, N = 6; Mann-Whitney test, p < 0.001; Figures 5C,D ).…”

Section: Resultsmentioning

confidence: 99%

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Schellino

Boido

Borsello

et al. 2018

Front. Mol. Neurosci.

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Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder that occurs in early childhood. The disease is caused by the deletion/mutation of the survival motor neuron 1 (SMN1) gene resulting in progressive skeletal muscle atrophy and paralysis, due to the degeneration of spinal motor neurons (MNs). Currently, the cellular and molecular mechanisms underlying MN death are only partly known, although recently it has been shown that the c-Jun NH2-terminal kinase (JNK)-signaling pathway might be involved in the SMA pathogenesis. After confirming the activation of JNK in our SMA mouse model (SMN2+/+; SMNΔ7+/+; Smn−/−), we tested a specific JNK-inhibitor peptide (D-JNKI1) on these mice, by chronic administration from postnatal day 1 to 10, and histologically analyzed the spinal cord and quadriceps muscle at age P12. We observed that D-JNKI1 administration delayed MN death and decreased inflammation in spinal cord. Moreover, the inhibition of JNK pathway improved the trophism of SMA muscular fibers and the size of the neuromuscular junctions (NMJs), leading to an ameliorated innervation of the muscles that resulted in improved motor performances and hind-limb muscular tone. Finally, D-JNKI1 treatment slightly, but significantly increased lifespan in SMA mice. Thus, our results identify JNK as a promising target to reduce MN cell death and progressive skeletal muscle atrophy, providing insight into the role of JNK-pathway for developing alternative pharmacological strategies for the treatment of SMA.

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“…SMA has traditionally been considered a motor neuron disease. However, this view has evolved as defects in multiple non‐neuronal cell types have been identified . It is unclear whether extra‐neuronal components contribute to the clinical picture of SMA (reviewed in ), but they may become particularly relevant for SMA patients where restoration of SMN protein, largely in the nervous system, has been achieved through therapeutic intervention (e.g.…”

Section: Introductionmentioning

confidence: 99%

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

Deguise

Baranello

Mastella

et al. 2019

Ann Clin Transl Neurol

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118

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Objective Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder leading to paralysis and subsequent death in young children. Initially considered a motor neuron disease, extra‐neuronal involvement is increasingly recognized. The primary goal of this study was to investigate alterations in lipid metabolism in SMA patients and mouse models of the disease. Methods We analyzed clinical data collected from a large cohort of pediatric SMA type I–III patients as well as SMA type I liver necropsy data. In parallel, we performed histology, lipid analysis, and transcript profiling in mouse models of SMA. Results We identify an increased susceptibility to developing dyslipidemia in a cohort of 72 SMA patients and liver steatosis in pathological samples. Similarly, fatty acid metabolic abnormalities were present in all SMA mouse models studied. Specifically, Smn2B/‐ mice displayed elevated hepatic triglycerides and dyslipidemia, resembling non‐alcoholic fatty liver disease (NAFLD). Interestingly, this phenotype appeared prior to denervation. Interpretation This work highlights metabolic abnormalities as an important feature of SMA, suggesting implementation of nutritional and screening guidelines in patients, as such defects are likely to increase metabolic distress and cardiovascular risk. This study emphasizes the need for a systemic therapeutic approach to ensure maximal benefits for all SMA patients throughout their life.

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New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Cited by 38 publications

References 80 publications

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

Muscle overexpression of Klf15 via an AAV8-Spc5-12 construct does not provide benefits in spinal muscular atrophy mice

Pharmacological c-Jun NH2-Terminal Kinase (JNK) Pathway Inhibition Reduces Severity of Spinal Muscular Atrophy Disease in Mice

Abnormal fatty acid metabolism is a core component of spinal muscular atrophy

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