Frontotemporal lobar degeneration (FTLD)2 is the second most common dementing disorder in patients under 65 years of age and is characterized by progressive atrophy of the frontal and temporal lobes in the brain. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration. In 2006, TAR DNA-binding protein of 43 kDa (TDP-43) was identified as the major component of tau-negative, ubiquitin-positive inclusions in these diseases (1, 2). TDP-43 is a heterogeneous nuclear ribonucleoprotein of 414 amino acids, originally identified as a transcriptional repressor that binds to the transactivation-responsive region of the HIV-1 gene (3). It is expressed ubiquitously and is localized mainly in nuclei, functioning in exon splicing, gene transcription, regulation of mRNA stability and biosynthesis, and the formation of nuclear bodies. For example, it has been reported that TDP-43 binds to the junctional region between exons 9 and 10 of the gene coding cystic fibrosis transmembrane conductance regulator and causes skipping of exon 9 (4). Structurally, TDP-43 is characterized by two RNA-recognition motifs, a C-terminal tail that contains a glycine-rich region and a glutamine/asparagine (Gln/Asn)-rich region.Discovery of missense mutations in the TARBDP gene in patients with familial and sporadic ALS and FTLD (5-12) demonstrated a direct link between genetic lesions and development of TDP-43 pathology. Importantly, most of the mutations are localized in the carboxyl-third of the molecule, which shows sequence similarity to prion proteins. Furthermore, biochemical and histological analyses demonstrated accumulation of full-length and C-terminal fragments (CTFs) in hyperphosphorylated and fibrillar forms in brain and spinal cord of patients (13). Furthermore, the CTF-banding patterns are different between the diseases and are closely related to the neuropathological phenotypes, which can be classified into at least four groups (types A-D) (13,14). The CTF-banding patterns are considered to reflect the protease resistance of the assembled protein structures (15). It was recently demonstrated that the pathological TDP-43 has prion-like activity and can convert normal TDP-43 to an abnormal form in cultured cells (16). Interestingly, the CTF-banding patterns of converted host proteins resemble those of the pathological TDP-43 used as seeds, suggesting that the conversion is template-dependent.These findings strongly suggest that aggregation of C-terminal regions of TDP-43 plays a central role in the pathogenesis and progression of ALS and FTLD with TDP-43 pathologies (FTLD-TDP). The aggregation of CTFs of TDP-43 has also been demonstrated in experimental cellular models; for example, our previous study showed that expression of CTF(162-414) of TDP-43 with a GFP tag in SH-SY5Y cells induced cytosolic mislocalization of TDP-43 in phosphorylated and ubiquitinated aggregates, recapitulating the TDP-43 pathology in brains (17).

A BS TRACT: Background: The α-Synuclein (α-Syn) V15A variant has been found in two Caucasian families with Parkinson's disease (PD). However, the significance of this missense variant remained unclear. Objective: We sought to elucidate whether V15A could increase aggregation or change phospholipid affinity. Methods: A sequencing analysis for the SNCA encoding α-Syn from 875 patients with PD and 324 control subjects was performed. Comparing with known pathogenic missense variants of α-Syn, A30P, and A53T, we analyzed the effects of V15A on binding to phospholipid membrane, self-aggregation, and seed-dependent aggregation in cultured cells. Results: Genetic screening identified SNCA c.44 T>C (p.V15A) from two Japanese PD families. The missense variant V15A was extremely rare in several public databases and predicted as pathogenic using in silico tools. The amplification activity of α-Syn V15A fibrils was stronger than that of wild-type α-Syn fibrils. Conclusions: The discovery of the V15A variant from Japanese families reinforces the possibility that the V15A variant may be a causative variant for developing PD. V15A had a reduced affinity for phospholipids and increased propagation activity compared with wild-type.

Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions.

Type2 diabetes mellitus (T2DM) has long been considered a risk factor for Alzheimer's disease (ad). However, the molecular links between T2DM and ad remain obscure. Here, we reported that serum/glucocorticoid-regulated kinase1 (SGK1) is activated by administering a chronic high-fat diet (HFD), which increases the risk of T2DM, and thus promotes Tau pathology via the phosphorylation of tau at Ser214 and the activation of a key tau kinase, namely, GSK-3ß, forming SGK1-GSK-3ß-tau complex. SGK1 was activated under conditions of elevated glucocorticoid and hyperglycemia associated with HFD, but not of fatty acid-mediated insulin resistance. Elevated expression of SGK1 in the mouse hippocampus led to neurodegeneration and impairments in learning and memory. Upregulation and activation of SGK1, SGK1-GSK-3ß-tau complex were also observed in the hippocampi of ad cases. Our results suggest that SGK1 is a key modifier of tau pathology in ad, linking ad to corticosteroid effects and T2DM.