CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

No abstract

Intracellular filamentous tau pathology is the defining feature of tauopathies, which form a subset of neurodegenerative diseases. We have analyzed pathological tau in Alzheimer’s disease, and in frontotemporal lobar degeneration associated with tauopathy to include cases with Pick bodies, corticobasal degeneration, progressive supranuclear palsy, and ones due to intronic mutations in MAPT. We found that the C-terminal band pattern of the pathological tau species is distinct for each disease. Immunoblot analysis of trypsin-resistant tau indicated that the different band patterns of the 7–18 kDa fragments in these diseases likely reflect different conformations of tau molecular species. Protein sequence and mass spectrometric analyses revealed the carboxyl-terminal region (residues 243–406) of tau comprises the protease-resistant core units of the tau aggregates, and the sequence lengths and precise regions involved are different among the diseases. These unique assembled tau cores may be used to classify and diagnose disease strains. Based on these results, we propose a new clinicopathological classification of tauopathies based on the biochemical properties of tau.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1503-3) contains supplementary material, which is available to authorized users.

No abstract

These observations suggest the hypothesis that underexpression of miR-29a affects neurodegenerative processes by enhancing neuronal NAV3 expression in AD brains.

No abstract

Increasing evidence suggests that ␣-synuclein is a common pathogenic molecule in several neurodegenerative diseases, particularly in Parkinson's disease. To understand ␣-synuclein pathology, we investigated molecules that interact with ␣-synuclein in human and rat brains and identified tubulin as an ␣-synuclein binding-/associated protein. Tubulin co-localized with ␣-synuclein in Lewy bodies and other ␣-synuclein-positive pathological structures. Tubulin initiated and promoted ␣-synuclein fibril formation under physiological conditions in vitro. These findings suggest that an interaction between tubulin and ␣-synuclein might accelerate ␣-synuclein aggregation in diseased brains, leading to the formation of Lewy bodies. The non-␤-amyloid (A␤)1 component of Alzheimer's disease amyloid, or NAC, originally detected in an amyloid-enriched fraction, was shown to be a fragment of its precursor, NACP, by cloning of the full-length cDNA (1). Later, NACP turned out to be a human homologue of Torpedo synuclein (2). Therefore, it is also referred to as human ␣-synuclein (3). ␣-Synuclein is abundant in presynaptic terminals of neurons (4). Recently, two missense mutations in the ␣-synuclein gene (5) were discovered in certain pedigrees with familial Parkinson's disease and were shown to segregate with the illness (6, 7). Shortly thereafter, ␣-synuclein was identified as the major filamentous component of Lewy bodies (LBs) in Parkinson's disease (8, 9) and of cytoplasmic inclusions in multiple system atrophy (MSA) (10 -12).Thus, ␣-synuclein appears to be a common pathogenic molecule in these diseases.Although the physiological role of ␣-synuclein is unknown, ␣-synuclein has the property of forming fibrils by itself in vitro, and mutations of ␣-synuclein accelerate the fibril formation (13,14). However, the vast majority of cases of neurodegenerative diseases associated with LBs or with ␣-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies (DLB), MSA, and the LB variant of Alzheimer's disease, are sporadic, where wild-type ␣-synuclein has shown to be abnormally accumulated as fibrillar structures. It is therefore likely that at some stage(s) in the fibril formation of ␣-synuclein, either the nucleation and/or the elongation steps should be somehow accelerated in diseased brains, or alternatively, some degradation process(es) of abnormal structures of ␣-synuclein might be defective in those patients (15).With respect to the amyloidogenesis of Alzheimer's disease, it was demonstrated in vitro that a seed of NAC can accelerate A␤ fibril formation, and conversely, a seed of A␤ can promote NAC fibril formation (16). Similarly, heterogeneous molecules could also be involved in the formation of ␣-synuclein fibrils, leading to pathological structures of ␣-synuclein such as LBs.In this study, we performed a biochemical investigation of molecules that interact with ␣-synuclein in the human brain, and we identified tubulin as one of the ␣-synuclein binding/ associated proteins. This interaction was confirmed by co...

We examined neuronal cytoplasmic inclusions (NCIs) and oligodendrocytic glial cytoplasmic inclusions (GCIs) in the pontine nuclei in multiple system atrophy (MSA) using antibodies against the non-amyloid beta component of Alzheimer's disease amyloid precursor protein (NACP/alpha-synuclein). Our immunohistochemical study revealed that anti-NACP antibodies labeled both NCIs and GCIs. Immunoelectron microscopy showed that positive reaction products were localized on the 15- to 30-nm-thick filamentous components of NCIs and GCIs. The present study demonstrates that NACP is associated with cytoplasmic inclusions of MSA, and suggests a role of NACP in abnormal filament aggregation in neuronal degeneration.