bims-polyam 2024-03-10 papers

Issue of 2024–03–10
three papers selected by
Sebastian J. Hofer, University of Graz

Sci Rep. 2024 Mar 08. 14(1): 5765

Loss-of-function variant in spermidine/spermine N1-acetyl transferase like 1 (SATL1) gene as an underlying cause of autism spectrum disorder.

Abdulfatah M Alayoubi, Muhammad Iqbal, Hassan Aman, Jamil A Hashmi, Laila Alayadhi, Khalid Al-Regaiey, Sulman Basit.

Autism spectrum disorder (ASD) is a complicated, lifelong neurodevelopmental disorder affecting verbal and non-verbal communication and social interactions. ASD signs and symptoms appear early in development before the age of 3 years. It is unlikely for a person to acquire autism after a period of normal development. However, we encountered an 8-year-old child who developed ASD later in life although his developmental milestones were normal at the beginning of life. Sequencing the complete coding part of the genome identified a hemizygous nonsense mutation (NM_001367857.2):c.1803C>G; (p.Tyr601Ter) in the gene (SATL1) encoding spermidine/spermine N1-acetyl transferase like 1. Screening an ASD cohort of 28 isolated patients for the SATL1 gene identified another patient with the same variant. Although SATL1 mutations have not been associated with any human diseases, our data suggests that a mutation in SATL1 is the underlying cause of ASD in our cases. In mammals, mutations in spermine synthase (SMS), an enzyme needed for the synthesis of spermidine polyamine, have been reported in a syndromic form of the X-linked mental retardation. Moreover, SATL1 gene expression studies showed a relatively higher expression of SATL1 transcripts in ASD related parts of the brain including the cerebellum, amygdala and frontal cortex. Additionally, spermidine has been characterized in the context of learning and memory and supplementations with spermidine increase neuroprotective effects and decrease age-induced memory impairment. Furthermore, spermidine biosynthesis is required for spontaneous axonal regeneration and prevents α-synuclein neurotoxicity in invertebrate models. Thus, we report, for the first time, that a mutation in the SATL1 gene could be a contributing factor in the development of autistic symptoms in our patients.

Keywords: Exome sequencing; Late onset ASD; Mutation; Polyamines

DOI: https://doi.org/10.1038/s41598-024-56253-5

Mol Brain. 2024 Mar 05. 17(1): 15

Spermidine treatment: induction of autophagy but also apoptosis?

Maxinne Watchon, Amanda L Wright, Holly I Ahel, Katherine J Robinson, Stuart K Plenderleith, Andrea Kuriakose, Kristy C Yuan, Angela S Laird.

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.

Keywords: Autophagy; Machado-Joseph disease; Neurodegeneration; PolyQ; Spinocerebellar ataxia type 3; Trinucleotide repeat disease; Zebrafish

DOI: https://doi.org/10.1186/s13041-024-01085-7

Curr Med Sci. 2024 Mar 08.

Possible Role of Cellular Polyamine Metabolism in Neuronal Apoptosis.

Xin-Tong Ji, Wen-Lei Yu, Meng-Jia Jin, Lin-Jie Lu, Hong-Ping Yin, Huan-Huan Wang.

Recent studies have shown that cellular levels of polyamines (PAs) are significantly altered in neurodegenerative diseases. Evidence from in vivo animal and in vitro cell experiments suggests that the cellular levels of various PAs may play important roles in the central nervous system through the regulation of oxidative stress, mitochondrial metabolism, cellular immunity, and ion channel functions. Dysfunction of PA metabolism related enzymes also contributes to neuronal injury and cognitive impairment in many neurodegenerative diseases. Therefore, in the current work, evidence was collected to determine the possible associations between cellular levels of PAs, and related enzymes and the development of several neurodegenerative diseases, which could provide a new idea for the treatment of neurodegenerative diseases in the future.

Keywords: apoptosis; mitochondria; neurodegenerative disease; polyamine

DOI: https://doi.org/10.1007/s11596-024-2843-9