Immunohistochemical Study of Human Mitochondrial Ferritin in the Substantia Nigra Following Subarachnoid Hemorrhage.

Mitochondrial ferritin (FtMt) is a novel ferritin that sequesters iron and plays a protective role against oxidative stress. FtMt shares a high homology with H-ferritin but is expressed only in the brain, heart, and testis. In the midbrain, FtMt expression is observed in the substantia nigra. FtMt plays a neuroprotective role in the pathology of neurodegenerative diseases such as Parkinson's disease, where excessive iron induces oxidative stress, causing cell death. Herein, we investigated FtMt immunoreactivity in the brains of patients with subarachnoid hemorrhage (SAH). Double immunofluorescence labeling of tyrosine hydroxylase (TH) and FtMt showed high colocalization in the substantia nigra pars compacta (SNc) in control and SAH cases. However, in SAH cases, FtMt immunoreactivity was observed in some TH-negative neurons. Double immunofluorescence labeling of glial cell markers and FtMt showed no apparent colocalization. The number and ratio of FtMt-positive but TH-negative neurons significantly differed between the control and SAH groups. Prussian blue staining in SAH cases showed positive iron staining over a wide surface range and the substantia nigra. Thus, FtMt may be related to iron dynamics in the substantia nigra following subarachnoid hemorrhage.

Immunohistochemical Analysis of Mitochondrial Ferritin in the Midbrain of Patients with Parkinson's Disease.

Mitochondrial ferritin (FtMt) is an endogenous iron-storage protein localized in the mitochondria. FtMt is mainly observed in restricted tissues, such as those in the testis, islets of Langerhans, and brain. Further, it may protect cells from oxidative stress in neurodegenerative diseases, including Alzheimer's disease and progressive supranuclear palsy. However, the role of FtMt in Parkinson's disease (PD) remains unclear. Therefore, the current study investigated the localization and expression level of FtMt in the midbrain of patients with PD and healthy controls using immunohistochemical techniques. FtMt immunoreactivity was mainly detected in dopaminergic neurons in the substantia nigra pars compacta (SNc) in both healthy controls and patients with PD. In addition, FtMt-positive particles were observed outside the dopaminergic neurons in patients with PD. Based on a quantitative comparison, patients with PD had a significantly upregulated FtMt immunoreactivity in dopaminergic neurons than healthy controls. Our result might be helpful in future studies on the role of FtMt in PD.

Thioredoxin-Interacting Protein (TXNIP) with Focus on Brain and Neurodegenerative Diseases.

The development of new therapeutic approaches to diseases relies on the identification of key molecular targets involved in amplifying disease processes. One such molecule is thioredoxin-interacting protein (TXNIP), also designated thioredoxin-binding protein-2 (TBP-2), a member of the α-arrestin family of proteins and a central regulator of glucose and lipid metabolism, involved in diabetes-associated vascular endothelial dysfunction and inflammation. TXNIP sequesters reduced thioredoxin (TRX), inhibiting its function, resulting in increased oxidative stress. Many different cellular stress factors regulate TXNIP expression, including high glucose, endoplasmic reticulum stress, free radicals, hypoxia, nitric oxide, insulin, and adenosine-containing molecules. TXNIP is also directly involved in inflammatory activation through its interaction with the nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) inflammasome complex. Neurodegenerative diseases such as Alzheimer's disease have significant pathologies associated with increased oxidative stress, inflammation, and vascular dysfunctions. In addition, as dysfunctions in glucose and cellular metabolism have been associated with such brain diseases, a role for TXNIP in neurodegeneration has actively been investigated. In this review, we will focus on the current state of the understanding of possible normal and pathological functions of TXNIP in the central nervous system from studies of in vitro neural cells and the brains of humans and experimental animals with reference to other studies. As TXNIP can be expressed by neurons, microglia, astrocytes, and endothelial cells, a complex pattern of regulation and function in the brain is suggested. We will examine data suggesting TXNIP as a therapeutic target for neurodegenerative diseases where further research is needed.