Ddhd1 knockout mouse as a model of locomotive and physiological abnormality in familial spastic paraplegia

We have previously reported a novel homozygous 4-bp deletion in DDHD1 as the responsible variant for spastic paraplegia type 28 (SPG28; OMIM#609340). The variant causes a frameshift, resulting in a functionally null allele in the patient. DDHD1 encodes phospholipase A1 (PLA1) catalyzing phosphatidylinositol to lysophosphatidylinositol (LPI). To clarify the pathogenic mechanism of SPG28, we established Ddhd1 knockout mice (Ddhd1[−/−]) carrying a 5-bp deletion in Ddhd1, resulting in a premature termination of translation at a position similar to that of the patient. We observed a significant decrease in foot–base angle (FBA) in aged Ddhd1(−/−) (24 months of age) and a significant decrease in LPI 20:4 (sn-2) in Ddhd1(−/−) cerebra (26 months of age). These changes in FBA were not observed in 14 months of age. We also observed significant changes of expression levels of 22 genes in the Ddhd1(−/−) cerebra (26 months of age). Gene Ontology (GO) terms relating to the nervous system and cell–cell communications were significantly enriched. We conclude that the reduced signaling of LPI 20:4 (sn-2) by PLA1 dysfunction is responsible for the locomotive abnormality in SPG28, further suggesting that the reduction of downstream signaling such as GPR55 which is agonized by LPI is involved in the pathogenesis of SPG28.

Clinical Presentation and Aetiology of Myelopathy

Introduction: Diseases of the spinal cord are called myelopathy. They are frequently devastating. They produce quadriplegia or paraplegia with sensory deficits far beyond the site of damage. Many spinal cord diseases are reversible if recognized and treated at an early stage.Objectives: The aim of this study was to evaluate clinical presentation and aetiology of myelopathy among the patients attending Rajshahi Medical College Hospital with the help of history, clinical examination and investigations.Methodology: This was a cross-sectional type of descriptive study. A total 44 myelopathic patients were evaluated between January 2009 to December 2009.Result: Out of 44 patients, 33 (75%) were male and 11 (25%) were female (ratio 3:1), mean aged 35 ± 13.9 years (range 13-65 years). Among them 24 (54.5%) patients had paraparesis and 20 (45.5%) patients had quadriparesis. It was observed that majority 33 (75%) of them had compressive type and 11 (25%) patients had non-compressive type of involvement. Out of 33 compressive myelopathy, the commonest cause was cervical spondylotic myelopathy 14 (42.4%) in number. 2nd cause was Pott’s disease 8 (24.2%) in number. Syringomyelia was detected in 5 (11.4%) patients, disc herniation was in 2 (6.1%) patients, schwannoma was in 2 (6.1%) patients, lipoma was in 1 (3%) patient and 1 (3%) patient was metastasis to the vertebra. Out of 11 non-compressive myelopathy, acute transverse myelitis was detected in 9 (81.8%) patients and familial spastic paraplegia in 2 (18.2%) patients.Conclusion: All patients with myelopathy should be investigated for potentially treatable causes.TAJ 2013; 26: 48-52

Increased expression of AT-1/SLC33A1 causes an autistic-like phenotype in mice by affecting dendritic branching and spine formation

The import of acetyl-CoA into the lumen of the endoplasmic reticulum (ER) by AT-1/SLC33A1 regulates Nε-lysine acetylation of ER-resident and -transiting proteins. Specifically, lysine acetylation within the ER appears to influence the efficiency of the secretory pathway by affecting ER-mediated quality control. Mutations or duplications in AT-1/SLC33A1 have been linked to diseases such as familial spastic paraplegia, developmental delay with premature death, and autism spectrum disorder with intellectual disability. In this study, we generated an AT-1 Tg mouse model that selectively overexpresses human AT-1 in neurons. These animals demonstrate cognitive deficits, autistic-like social behavior, aberrations in synaptic plasticity, an increased number of dendritic spines and branches, and widespread proteomic changes. We also found that AT-1 activity regulates acetyl-CoA flux, causing epigenetic modulation of the histone epitope H3K27 and mitochondrial adaptation. In conclusion, our results indicate that increased expression of AT-1 can cause an autistic-like phenotype by affecting key neuronal metabolic pathways.