The Role of Chorein Deficiency in Late Spermatogenesis.

VPS13A, also known as chorein, whose loss of function causes chorea-acanthocytosis (ChAc), is characterized by Huntington's-disease-like neurodegeneration and neuropsychiatric symptoms in addition to acanthocytosis in red blood cells. We previously reported that ChAc-model mice with a loss of chorein function exhibited male infertility, with asthenozoospermia and mitochondrial dysmorphology in the spermatozoa. Here, we report a novel aspect of chorein dysfunction in male fertility, particularly its role in spermatogenesis and mitochondrial integrity. An increase in anti-malondialdehyde antibody immunoreaction within the testes, predominantly observed at the advanced stages of sperm formation in chorein-deficient mice, suggests oxidative stress as a contributing factor to mitochondrial dysfunction and impaired sperm maturation. The chorein immunoreactivity in spermatids of wild-type mice accentuates its significance in sperm development. ChAc-model mice exhibit mitochondrial ultrastructural abnormalities, specifically during the late stages of sperm maturation, suggesting a critical timeframe for chorein's action in spermiogenesis. We observed an increase in TOM20 protein levels, indicative of disrupted mitochondrial import mechanisms. The concurrent decrease in metabolic enzymes such as IDH3A, LDHC, PGK2, and ACAT1 suggests a complex chorein-mediated metabolic network that is essential for sperm vitality. Additionally, heightened separation of cytoplasmic droplets from sperm highlights the potential membrane instability in chorein-deficient spermatozoa. Metabolomic profiling further suggests a compensatory metabolic shift, with elevated glycolytic and TCA-cycle substrates. Our findings suggest that chorein is involved in anti-ferroptosis and the maturation of mitochondrial morphology in the late stages of spermatogenesis, and its deficiency leads to asthenozoospermia characterized by membrane instability, abnormal cytosolic glycolysis, abnormal mitochondrial function, and a disrupted TCA cycle. Further analyses are required to unravel the molecular mechanisms that directly link these findings and to elucidate the role of chorein in spermatogenesis as well as its broader implications.

Aging-Related Catatonia with Reversible Dopamine Transporter Dysfunction in Females with Depressive Symptoms: A Case Series.

OBJECTIVES: The authors describe five depressive patients with initially decreased striatal accumulation of dopamine transporter (DAT) single-photon emission computed tomography (SPECT), which improved in parallel with clinical symptoms. METHODS: Patients who exhibited decreased striatal accumulation and recovery of DATSPECT were identified among patients with the symptoms of depression. Their clinical and neuroimaging data were reviewed. RESULTS: Five patients were identified. All patients were presenile or senile women who presented with catatonia subsequent to symptoms of depression that remitted with treatment. DAT-SPECT showed a decreased striatal accumulation in all patients, which increased after treatment. Two patients had met the diagnostic criteria of probable dementia with Lewy bodies (DLB), but no longer did so after their symptoms improved. CONCLUSIONS: Reversible DAT dysfunction observed in this study suggests that reversible impairment of dopaminergic transmission in the striatum partly underlies catatonia. Careful consideration should be given to diagnosing DLB in patients with decreased DAT-SPECT accumulation, especially when catatonia is present.

Association of auditory Charles Bonnet syndrome with increased blood flow in the nondominant Brodmann area 22.

Aim: Auditory Charles Bonnet syndrome (aCBS) is characterized by musical hallucinations (MHs) that accompany acquired hearing impairments. This hallucination is the acoustic perception of music, sounds, or songs in the absence of an outside stimulus, and it may be associated with hyperactivity of the superior temporal lobes. Some studies have reported the possibility of improving MH with antiepileptics. To elucidate in detail the brain regions responsible for aCBS, we analyzed the regions that changed functionally after treatment. Methods: Before and after treatment with carbamazepine (four cases), clonazepam (one case), and a hearing aid (one case), cerebral perfusion single-photon emission computed tomography (SPECT) and the Auditory Hallucination Rating Scale (AHRS) were applied to six patients with hearing-loss-associated MHs. Results: Cerebral blood flow analysis using SPECT revealed hyperperfusion in Brodmann area (BA) 22-the posterior region of the superior temporal gyrus-in the nondominant hemisphere in all six patients in the pretreatment phase. After treatment, the hyperperfusion region improved in all patients. The area percentages with hyperperfusion in the nondominant BA22 were strongly positively correlated with the AHRS score. Conclusion: The results suggest that aCBS, which was treatable with antiepileptics or hearing aids, was involved in hyperexcitement in BA22, and that MH strength was correlated with degree of excitement.

Mouse model of chorea-acanthocytosis exhibits male infertility caused by impaired sperm motility as a result of ultrastructural morphological abnormalities in the mitochondrial sheath in the sperm midpiece.

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis caused by loss-of-function mutations in the Vacuolar Protein Sorting 13 Homolog A (VPS13A) gene, which encodes chorein. We previously produced a ChAc-model mouse with a homozygous deletion of exons 60-61 in Vps13a, which corresponded to the human disease mutation. We found that male ChAc-model mice exhibited complete infertility as a result of severely diminished sperm motility. Immunocytochemical study revealed that chorein-like immunoreactivity is abundant only in the midpiece, mitochondria-rich region, of the sperm of wild type mice. They showed no significant differences from wild types in terms of the adenosine 5'-triphosphate (ATP) concentration of their sperm, sperm count, or sexual activity. Electron microscopy revealed abnormal ultrastructural morphology of the mitochondria in the midpiece of sperm from ChAc-model mice. These results suggest that chorein is essential in mouse sperm for the maintenance of ultrastructural mitochondrial morphology and sperm motility.

Phenotypic abnormalities in a chorea-acanthocytosis mouse model are modulated by strain background.

Chorea-acanthocytosis (ChAc) is an autosomal recessive hereditary disease characterized by neurodegeneration in the striatum and acanthocytosis that is caused by mutations in the VPS13A gene. We previously produced a ChAc model mice encoding a human disease mutation with deletion of exons 60-61 in the VPS13A gene. The behavioral and pathological phenotypes of the model mice varied a good deal from individual to individual, indicating that differences between individuals may be caused by the content of a genetic hybrid 129/Sv and C57BL/6J strain background. To establish the effect of the genetic background on phenotype, we backcrossed the ChAc-model mice to different inbred strains: C57BL/6J and 129S6/Sv. Although no significant difference between ChAc-mutant mice and wild-type mice on the C57BL/6J background was observed, the ChAc-mutant mice on the 129S6/Sv showed abnormal motor function and behavior. Furthermore, we produced ChAc-mutant mice on two different inbred strains: BALB/c and FVB. Significant reduction in weight was observed in ChAc mutant mice on the FVB and 129S6 backgrounds. We found a marked increase in the osmotic fragility of red blood cells in the ChAc mutant mice backcrossed to 129S6/Sv and FVB. The phenotypes varied according to strain, with ChAc mutant mice on the FVB and 129S6 backgrounds showing remarkably abnormal motor function and behavior. These results indicate that there are modifying genetic factors of ChAc symptoms.