Abstract
Mitochondrial ferritin (FtMt) is a mitochondrial iron storage protein associated with neurodegenerative diseases. In patients with progressive supranuclear palsy (PSP), FtMt was shown to accumulate in nigral neurons. Here, we investigated FtMt and LC3 in the post-mortem midbrain of PSP patients to reveal novel aspects of the pathology. Immunohistochemistry was used to assess the distribution and abnormal changes in FtMt and LC3 immunoreactivities. Colocalization analysis using double immunofluorescence was performed, and subcellular patterns were examined using 3D imaging and modeling. In the substantia nigra pars compacta (SNc), strong FtMt-IR and LC3-IR were observed in the neurons of PSP patients. In other midbrain regions, such as the superior colliculus, the FtMt-IR and LC3-IR remained unchanged. In the SNc, nigral neurons were categorized into four patterns based on subcellular LC3/FtMt immunofluorescence intensities, degree of colocalization, and subcellular overlapping. This categorization suggested that concomitant accumulation of LC3/FtMt is related to mitophagy processes. Using the LC3-IR to stage neuronal damage, we retraced LC3/FtMt patterns and revealed the progression of FtMt accumulation in nigral neurons. Informed by these findings, we proposed a hypothesis to explain the function of FtMt during PSP progression.
Highlights
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder with3–4 cases per million people reported annually
Single immunostaining for FtMt and LC3 were performed on paraffin-embedded sections of midbrains from control and PSP patient cases
We report the abnormal accumulation of LC3, an autophagosomal marker, in the same neurons
Summary
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder with3–4 cases per million people reported annually. Progressive supranuclear palsy (PSP) is a rare neurodegenerative disorder with. Like Parkinson’s disease, the pathological features of PSP include loss of nigral neurons [1]. PSP accounts for approximately 5% of Parkinson’s disease incidence [2] and is the most common form of atypical parkinsonism [3]. PSP cases are predicted to increase from 2030 [4]; accurate diagnosis remains difficult and a cure is yet to be found [5]. PSP is a tauopathy with considerable accumulation of four-repeat tau and formation of aberrant tau structures (neurofibril tangles, globose-type tangles, fine threads, and small dot structures) appearing as additional major pathological features [6,7]. Mitochondrial dysfunction is frequently associated with PSP [8,9] and could be used to leverage the development of novel diagnostic methods
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