No abstract

Mutations in Parkinson disease (PD)3 is a major neurodegenerative disease of the adulthood affecting the extrapyramidal motor system (1). The brains of patients affected with PD are characterized by a loss of neurons in the brainstem monoaminergic neurons, e.g. dopamine neurons in the substantia nigra and noradrenergic neurons in the locus caeruleus, which is accompanied by the deposition of Lewy bodies (LBs) in the cytoplasm of remaining neurons. LBs are characteristic spherical intracytoplasmic inclusions composed of filaments of ϳ7-10 nm in diameter and are pathognomonic for PD and related dementing disorder, dementia with Lewy bodies (DLB) (2). A small percentage of patients inherit PD as an autosomal dominant trait (familial PD; FPD), and missense mutations (3-5) or multiplications (6 -8) of the ␣-synuclein gene have been identified in these families. LBs in the brains of patients with sporadic PD or DLB were shown to be composed of ␣-synuclein (9, 10). Glial cytoplasmic inclusions in the brains of patients with multiple system atrophy, another major sporadic neurodegenerative disease, or dystrophic neurites in Hallervorden-Spatz disease also were shown to be composed of ␣-synuclein, and these neurodegenerative diseases characterized by deposition of ␣-synuclein are collectively designated "synucleinopathies" (2). In vitro studies suggested that ␣-synuclein aggregates and forms filaments that are similar to those seen in PD or DLB brains, and amino acid substitutions linked to familial PD (A53T, A30P, or E46K) have been shown to enhance the aggregation of ␣-synuclein possibly through conformational changes (11-14), implicating deposition of ␣-synuclein in the pathogenesis of synucleinopathies including PD. Taken together with the gene dosage effects of ␣-synuclein in a subset of FPD (i.e. duplication and triplication), transgenic overexpression of ␣-synuclein in neurons would be a rational strategy to model neurodegeneration in PD.A number of transgenic models overexpressing ␣-synuclein using heterologous organisms Drosophila (21,22), Caenorhabditis elegans (23), yeast (24)) have been reported, and some abnormal behavioral or pathological phenotypes have been documented in a subset of these animal models. However, an ideal model in which deposition of ␣-synuclein in dopamine neurons, the most vulnerable subset of neurons in PD, causes behavioral phenotypes that are inherent to the functions of dopamine neurons, has not been established yet. Here we describe a transgenic C. elegans model in which human ␣-synuclein overexpressed specifically in dopamine neurons causes an abnormal phenotype in food-sensing behavior that has been attributed to the function of C. elegans dopamine neurons (25), in a manner dependent on FPD-linked mutations, through reduction of neuronal dopamine.

No abstract

Multiple system atrophy (MSA) is a fatal adult-onset neurodegenerative disease that is characterized by varying degrees of cerebellar dysfunction and Parkinsonism. The neuropathological hallmark of MSA is alpha-synuclein (AS)-positive glial cytoplasmic inclusions (GCIs). Although severe neuronal loss (NL) is also observed in MSA, neuronal inclusions (NIs) are rare compared to GCIs, such that the pathological mechanism of NL in MSA is unclear. GCIs and NIs are late-stage pathology features relative to AS oligomers and may not represent early pathological changes in MSA. To reveal the early pathology of MSA, it is necessary to examine the early aggregation of AS, i.e., AS oligomers. Here, we adopted a proximity ligation assay (PLA) to examine the distribution of AS oligomers in brain tissue samples from patients with MSA and other diseases. Surprisingly, MSA brains showed a widespread distribution and abundant accumulation of oligomeric AS in neurons as well as oligodendrocytes of the neocortex. In several regions, oligomeric AS signal intensity was higher in cases with MSA than in cases with Parkinson's disease. In contrast to previous studies, AS-PLA revealed abundant AS oligomer accumulation in Purkinje cells in MSA brains, identifying oligomeric AS accumulation as a possible cause of Purkinje cell loss. This wide distribution of AS oligomers in MSA brain neurons has not been described previously and indicates a pathological mechanism of NL in MSA.

The ␤-amyloid (A␤) precursor protein (APP) is cleaved sequentially by ␤-site of APP-cleaving enzyme (BACE) and ␥-secretase to release the A␤ peptides that accumulate in plaques in Alzheimer's disease (AD). GGA1, a member of the Golgi-localized ␥-ear-containing ARF-binding (GGA) protein family, interacts with BACE and influences its subcellular distribution. We now report that overexpression of GGA1 in cells increased the APP C-terminal fragment resulting from ␤-cleavage but surprisingly reduced A␤. GGA1 confined APP to the Golgi, in which fluorescence resonance energy transfer analyses suggest that the proteins come into close proximity. GGA1 blunted only APP but not notch intracellular domain release. These results suggest that GGA1 prevented APP ␤-cleavage products from becoming substrates for ␥-secretase. Direct binding of GGA1 to BACE was not required for these effects, but the integrity of the GAT (GGA1 and TOM) domain of GGA1 was. GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD.

Recent studies have revealed the clinical, histological, and pathophysiological characteristics in a group of inflammatory myopathies with selected autoantibodies. We retrospectively compared the clinical manifestations and histological features between 8 anti-mitochondrial (anti-M2) antibody-positive and 33 antibody-negative patients. Patients with anti-M2 antibodies have been previously reported to have delayed diagnostic confirmation and frequent cardiopulmonary complications in comparison to those without the antibodies. In our study, clinical characteristics in patients with the antibodies were as follows: lesser degree of limb muscle weakness and atrophy as well as lymphocytic infiltration in muscle biopsy specimens, and frequent paravertebral muscle atrophy. Anti-M2 antibody appeared to be a biomarker related to not only cardiopulmonary complications, but also characteristic ­distributions of affected muscles.

The pathological hallmarks of Parkinson’s disease (PD) are α-synuclein (αSYN)-positive inclusions referred to as Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology (LRP). LRP is thought to propagate in an ascending manner throughout the brain as the disease progresses. LRP is visible with histologic methods and is thought to represent a later stage of the disease process, while αSYN oligomers, which are not visible with routine histologic methods, are considered earlier. There is increasing evidence to suggest that αSYN oligomers may be more toxic than visible LRP. Detecting αSYN oligomers requires special techniques, and their distribution and association with clinical features are important research objectives. In this report, we describe the distribution of αSYN oligomers in multiple cortical and subcortical regions of PD using a proximity ligation assay (PLA). We observe widespread distribution of αSYN oligomers with PLA and more restricted distribution of LRP with αSYN immunohistochemistry. The distribution of αSYN oligomers differed from LRP in that αSYN oligomer burden was significantly greater in the neocortex, while LRP was greater in vulnerable subcortical regions, including the brainstem. We also found that cognitive impairment was associated with αSYN oligomers in the hippocampus. These results suggest that αSYN oligomers may be widely distributed in PD early in the disease process and that they may contribute to cognitive impairment in PD.

Collagenous Alzheimer amyloid plaque component (CLAC) is a unique non-Abeta amyloid component of senile plaques (SP) derived from a transmembrane collagen termed CLAC-precursor. Here we characterize the chronological and spatial relationship of CLAC with other features of SP amyloid in the brains of patients with Alzheimer's disease (AD), Down syndrome (DS), and of PSAPP transgenic mice. In AD and DS cerebral cortex, CLAC invariably colocalized with Abeta42 but often lacked Abeta40- or thioflavin S (thioS)-reactivities. Immunoelectron microscopy of CLAC-positive SP showed labeling of fibrils that are more loosely dispersed compared to typical amyloid fibrils in CLAC-negative SP. In DS cerebral cortex, diffuse plaques in young patients were negative for CLAC, whereas a subset of SP became CLAC-positive in patients aged 35 to 50 years, before the appearance of Abeta40. In DS cases over 50 years of age, Abeta40-positive SP dramatically increased, whereas CLAC burden remained at a constant level. In PSAPP transgenic mice, CLAC was positive in the diffuse Abeta deposits surrounding huge-cored plaques. Thus, CLAC and Abeta40 or thioS exhibit mostly separate distribution patterns in SP, suggesting that CLAC is a relatively early component of SP in human brains that may have inhibitory effects against the maturation of SP into beta-sheet-rich amyloid deposits.