Background: Distal hereditary motor neuronopathies (dHMN) are a group of genetic disorders characterised by motor neuron degeneration leading to muscle weakness that are caused by mutations in various genes. HMNJ is a distinct form of the disease that has been identified in patients from the Jerash region of Jordan. Our aim was to identify and characterise the genetic cause of HMNJ. Methods: We used whole exome and Sanger sequencing to identify a novel genetic variant associated with the disease and then carried out immunoblot, immunofluorescence and apoptosis assays to extract functional data and clarify the effect of this novel SIGMAR1 mutation. Physical and neurological examinations were performed on selected patients and unaffected individuals in order to re-evaluate clinical status of patients 20 years after the initial description of HMNJ as well as to evaluate new and previously undescribed patients with HMNJ. Results: A homozygous missense mutation (c.500A>T, N167I) in exon 4 of the SIGMAR1 gene was identified, cosegregating with HMNJ in the 27 patients from 7 previously described consanguineous families and 3 newly ascertained patients. The mutant SIGMAR1 exhibits reduced expression, altered subcellular distribution and elevates cell death when expressed. Conclusion: In conclusion, the homozygous SIGMAR1 c.500A>T mutation causes dHMN of the Jerash type, possibly due to a significant drop of protein levels. This finding is in agreement with other SIGMAR1 mutations that have been associated with autosomal recessive dHMN with pyramidal signs; thus, our findings further support that SIGMAR1 be added to the dHMN genes diagnostic panel.

The structurally and functionally complex Endoplasmic Reticulum (ER) hosts critical processes including lipid synthesis. Here, we focus on the functional characterization of transmembrane protein TMEM147 and report that it localizes at the ER and nuclear envelope in HeLa cells. Silencing of TMEM147 drastically reduces the level of lamin B receptor (LBR) at the Inner Nuclear Membrane and results in mistargeting of LBR to the ER. LBR possesses a modular structure and corresponding bifunctionality in heterochromatin organization, via its N-terminus, and cholesterol biosynthesis, via its sterol-reductase C-terminal domain. We show that TMEM147 physically interacts with LBR and the C-terminus of LBR is essential for their functional interaction. We find that TMEM147 also physically interacts with key sterol reductase DHCR7 in cholesterol biosynthesis. Similar to LBR, TMEM147 downregulation results in sharp decline of DHCR protein levels and co-ordinate transcriptional decrease of LBR and DHCR7 expression. Consistently, lipidomic analysis upon TMEM147 silencing identified changes in cellular cholesterol levels, cholesteryl ester levels and profile, and in cellular cholesterol uptake, raising the possibility that TMEM147 is an important new regulator of cholesterol homeostasis in cells.

Anoctamin 10 (ANO10), also known as TMEM16K, is a transmembrane protein and member of the anoctamin family characterized by functional duality. Anoctamins manifest ion channel and phospholipid scrambling activities and are involved in many physiological processes such as cell division, migration, apoptosis, cell signalling, and developmental processes. Several diseases, including neurological, muscle, blood disorders, and cancer, have been associated with the anoctamin family proteins. ANO10, which is the main focus of the present review, exhibits both scrambling and chloride channel activity; calcium availability is necessary for protein activation in either case. Additional processes implicating ANO10 include endosomal sorting, spindle assembly, and calcium signalling. Dysregulation of calcium signalling in Purkinje cells due to ANO10 defects is proposed as the main mechanism leading to spinocerebellar ataxia autosomal recessive type 10 (SCAR10), a rare, slowly progressive spinocerebellar ataxia. Regulation of the endolysosomal pathway is an additional ANO10 function linked to SCAR10 aetiology. Further functional investigation is essential to unravel the ANO10 mechanism of action and involvement in disease development.

Alzheimer’s disease (AD) is the most common neurodegenerative disease, affecting the elderly at a high incidence. AD is of unknown etiology and currently, no cure is available. Present medication is restricted to treating symptoms; thus, a need exists for the development of effective remedies. Medicinal plants constitute a large pool, from which active compounds of great pharmaceutical potential can be derived. Various Salvia spp. are considered as neuroprotective, and here, the ability of Salvia fruticosa (SF) to protect against toxic effects induced in an AD cell model was partly assessed. Two of AD’s characteristic hallmarks are the presence of elevated oxidative stress levels and the cytotoxic aggregation of amyloid beta (Aβ) peptides. Thus, we obtained SF extracts in three different solvents of increasing polarity, consecutively, to evaluate (a) their antioxidant capacity with the employment of the free radical scavenging assay (DPPH^•), of the ferric reducing ability of plasma assay (FRAP), and of the cellular reactive oxygen species assay (DCFDA) and (b) their neuroprotective properties against Aβ_25–35‐induced cell death with the use of an MTT assay. All three SF extracts showed a considerable antioxidant capacity, with the methanol (SFM) extract being the strongest. The results of the total phenolic and flavonoid contents (TPC and TFC) of the extracts and of the FRAP and the DCFDA assays showed a similar pattern. In addition, and most importantly, the dichloromethane (SFD) and the petroleum ether (SFP) extracts had an effect on Aβ toxicity, exhibiting a significant neuroprotective potential. To our knowledge, this is the first report of SF extracts demonstrating neuroprotective potential against Aβ toxicity. In combination with their antioxidant capacity, SF extracts may be beneficial in combating AD and other neurodegenerative diseases.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative condition, primarily affecting seniors. Despite the significant time and money spent over the past few decades, no therapy has been developed yet. In recent years, the research has focused on ameliorating the cytotoxic amyloid beta (Aβ) peptide aggregates and the increased elevated oxidative stress, two interconnected main AD hallmarks. Medicinal plants constitute a large pool for identifying bioactive compounds or mixtures with a therapeutic effect. Sideritis scardica (SS) has been previously characterized as neuroprotective toward AD. We investigated this ability of SS by generating eight distinct solvent fractions, which were chemically characterized and assessed for their antioxidant and neuroprotective potential. The majority of the fractions were rich in phenolics and flavonoids, and all except one showed significant antioxidant activity. Additionally, four SS extracts partly rescued the viability in Aβ_25–35-treated SH-SY5Y human neuroblastoma cells, with the initial aqueous extract being the most potent and demonstrating similar activity in retinoic-acid-differentiated cells as well. These extracts were rich in neuroprotective substances, such as apigenin, myricetin-3-galactoside, and ellagic acid. Our findings indicate that specific SS mixtures can benefit the pharmaceutical industry to develop herbal drugs and functional food products that may alleviate AD.