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We examined whether the Golgi apparatus (GA) is fragmented in nigral neurons in 18 cases with Parkinson's disease (PD) and in 8 control cases. The nigral neurons in cases with PD showed various degrees of Lewy pathology with alpha-synuclein immunohistochemistry, and we divided the neurons into three subtypes according to differences in alpha-synuclein immunoreactivity: (1) neurons without pale bodies or Lewy bodies, (2) neurons with pale bodies, and (3) neurons with Lewy bodies. In controls, we did not observe fragmented GA in nigral neurons by immunocytochemistry with an anti-TGN46 antibody. In PD, the GA was fragmented in 3% of the nigral neurons without inclusions, and in 5% of the neurons with Lewy bodies. In contrast, fragmented GA was noted in 19% of the neurons containing pale bodies. Since pale bodies represent early stages in the development of brainstem Lewy bodies, our results suggest that the cytotoxicity of alpha-synuclein-positive aggregates is reduced in the process of Lewy body formation.

Optineurin is a gene associated with normal tension glaucoma and primary open-angle glaucoma, one of the major causes of irreversible bilateral blindness. Recently, mutations in the gene encoding optineurin were found in patients with amyotrophic lateral sclerosis (ALS). Immunohistochemical analysis showed aggregation of optineurin in skein-like inclusions and round hyaline inclusions in the spinal cord, suggesting that optineurin appears to be a more general marker for ALS. However, our detailed examinations demonstrated that optineurin was found not only in ALS-associated pathological structures, but also in ubiquitin-positive intraneuronal inclusions in ALS with dementia, basophilic inclusions in the basophilic type of ALS, neurofibrillary tangles and dystrophic neurites in Alzheimer's disease, Lewy bodies and Lewy neurites in Parkinson's disease, ballooned neurons in Creutzfeldt-Jakob disease, glial cytoplasmic inclusions in multiple system atrophy, and Pick bodies in Pick disease. With respect to optineurin-positive basophilic inclusions, these structures showed variable immunoreactivities for ubiquitin; some structures were obviously ubiquitin-positive, while others were negative for the protein, suggesting that optineurin expression was not always associated with the expression of ubiquitin. This study indicates that optineurin is widely distributed in neurodegenerative conditions; however, its significance is obscure.

Initially, trans activation responsive region (TAR)-DNA-binding protein 43 (TDP-43) was considered to be a disease-specific component of ubiquitin-positive and tau-negative inclusions in the brains of patients with frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS); however, it is now widely known that this protein also abnormally accumulates in neurons in other neurodegenerative diseases. On the basis of observation mainly in the medial temporal lobe, TDP-43-immunoreactive neuronal inclusions have been detected in 20-30% of Alzheimer disease (AD) brains. However, it is controversial whether these cases represent a combined disease, that is, mixed AD/FTLD-U. To address this issue, it is necessary to obtain more knowledge on the region-specific distribution of TDP-43 immunoreactivity and also about its relationship to AD common pathology. Here, we describe abnormal TDP-43 immunoreactivity in the medial temporal lobe in 5/16 AD patients (31%). Most of the depositions were cytoplasmic inclusions, mainly located in the subiculum and parahippocampal gyrus and rarely in dentate granular cells of the hippocampus. TDP-43-positive inclusions and senile plaque/neurofibrillary tangle distribution were not always identical, and intracellular colocalizations of TDP-43 and phospho-tau were also infrequent. The cases showing TDP-43-positive inclusions in the medial temporal lobe also showed abnormally highly dense TDP-43 immunoreactivity in the frontal, but not in the parietal and occipital cortices. Intracellularly, TDP-43-positive inclusions were highly ubiquitinated and colocalized with p62 immunoreactivity as well. Our findings suggest that abnormal TDP-43 deposition and AD pathology (formation of senile plaques and neurofibrillary tangles) might occur independently. However, taken together with the results of previous reports, the distribution of TDP-43 immunoreactivity in the hippocampus and frontal cortex in AD appear to be varying. We consider that it is still too early to determine that the TDP-43 accumulation is a part of AD pathology or result from a completely independent pathology.

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