Several hundred proteins become insoluble and aggregation-prone as a consequence of aging in Caenorhabditis elegans. The data indicate that these proteins influence disease-related protein aggregation and toxicity.

Transgenic mice overexpressing the P301L mutant human tau protein exhibit an accumulation of hyperphosphorylated tau and develop neurofibrillary tangles. The consequences of tau pathology were investigated here by proteomics followed by functional analysis. Mainly metabolism-related proteins including mitochondrial respiratory chain complex components, antioxidant enzymes, and synaptic proteins were identified as modified in the proteome pattern of P301L tau mice. Significantly, the reduction in mitochondrial complex V levels in the P301L tau mice revealed using proteomics was also confirmed as decreased in human P301L FTDP-17 (frontotemporal dementia with parkinsonism linked to chromosome 17) brains. Functional analysis demonstrated a mitochondrial dysfunction in P301L tau mice together with reduced NADH-ubiquinone oxidoreductase activity and, with age, impaired mitochondrial respiration and ATP synthesis. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species in aged transgenic mice. Increased tau pathology as in aged homozygous P301L tau mice revealed modified lipid peroxidation levels and the upregulation of antioxidant enzymes in response to oxidative stress. Furthermore, P301L tau mitochondria displayed increased vulnerability toward ␤-amyloid (A␤) peptide insult, suggesting a synergistic action of tau and A␤ pathology on the mitochondria. Taken together, we conclude that tau pathology involves a mitochondrial and oxidative stress disorder possibly distinct from that caused by A␤. Alzheimer disease (AD)1 is characterized by two major histopathological hallmarks, extracellular plaques of fibrillar ␤-amyloid (A␤) peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein (1, 2). Mutations in tau have been identified in a related neurodegenerative disorder called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) with NFT formation in the absence of plaque formation (3-5). Transgenic mice overexpressing the P301L mutant human tau protein were created to model tauopathies in vivo (6, 7). These mice show an accumulation of hyperphosphorylated tau and NFT formation similar to those in FTDP-17 and AD.Little is known about the distinct intracellular mechanisms underlying the consequences of tau pathology. This insight could help us to understand the selective vulnerability of cells with tau pathology and thereby the pathogenesis of AD. Increasing evidence highlights a connection between AD and mitochondrial dysfunction together with a deregulation of energy metabolism and oxidative stress (8). Various reports have demonstrated markedly reduced levels of mitochondrial proteins and activities (9 -11), decreased glucose turnover (12, 13), increased mitochondrial DNA mutations (14 -16), and increased lipid peroxidation (17-19) in AD brains.To examine the contribution of tau to these neurodegenerative processes, we carried out a proteomic analysis of our P301L tau transgenic mice. To zoom in on proteins relevant to the p...

Filamentous inclusions composed of the microtubule-associated protein tau are a defining characteristic of a large number of neurodegenerative diseases. Here we show that tau degradation in stably transfected and non-transfected SH-SY5Y cells is blocked by the irreversible proteasome inhibitor lactacystin. Further, we find that in vitro, natively unfolded tau can be directly processed by the 20S proteasome without a requirement for ubiquitylation, and that a highly reproducible pattern of degradation intermediates is readily detectable during this process. Analysis of these intermediates shows that 20S proteasomal processing of tau is bi-directional, proceeding from both N-and C-termini, and that populations of relatively stable intermediates arise probably because of less efficient digestion of the C-terminal repeat region. Our results are consistent with an in vivo role for the proteasome in tau degradation and support the existence of ubiquitin-independent pathways for the proteasomal degradation of unfolded proteins.

Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 15 million people worldwide. Within the next generation, these numbers will more than double. To assist in the elucidation of pathogenic mechanisms of AD and related disorders, such as frontotemporal dementia , genetically modified mice, flies, fish and worms were developed, which reproduce aspects of the human histopathology, such as b-amyloidcontaining plaques and tau-containing neurofibrillary tangles (NFT). In mice, the tau pathology caused selective behavioral impairment, depending on the distribution of the tau aggregates in the brain. b-Amyloid induced an increase in the numbers of NFT, whereas the opposite was not observed in mice. In b-amyloid-producing transgenic mice, memory impairment was associated with increased levels of b-amyloid. Active and passive b-amyloid-directed immunization caused the removal of b-amyloid plaques and restored memory functions. These findings have since been translated to human therapy. This review aims to discuss the suitability and limitations of the various animal models and their contribution to an understanding of the pathophysiology of AD and related disorders. Keywords: Alzheimer's disease; frontotemporal dementia; b-amyloid; tau; transgenic; C. elegans; Drosophila; sea lamprey; mice; behavior; memory; therapy; immunization Alzheimer's disease and related disorders: neuropathology, genetics and clinical featuresIn 1907, the two key histopathological hallmarks of Alzheimer's disease (AD), b-amyloid plaques and neurofibrillary tangles (NFT), were for the first time described by Alois Alzheimer when he examined brain sections of his patient Auguste D. 1 Since then, the number of PubMed entries for 'Alzheimer' steadily increased and, in 2002 alone, added up to 5213 entries. The last 20 years of AD research, with the help of animal models, assisted in the elucidation of aspects of the pathophysiology of AD and the relationship of the two major lesions. Parallel to this increased insight into disease mechanisms, the number of AD patients is rising as the numbers of old people are increasing in many countries. Moreover, the incidence of AD rises from less than 2% for people under the age of 60 to about 30% in people older than 85. 2 b-Amyloid plaques and Ab processing b-Amyloid plaques are one of the histopathological hallmarks of AD. The term amyloid has been introduced to describe a heterogeneous class of protein aggregates with a b-pleated sheet secondary structure, which confers affinity to the histochemical dye congo red. In AD, b-amyloid is deposited around meningeal and cerebral vessels, and in the gray matter as b-amyloid plaques. The major proteinaceous component is a 40-42 amino-acid polypeptide termed Ab (Ab 40 and Ab 42 ), which is derived by proteolysis from the amyloid precursor protein (APP). 3,4 APP can be proteolytically cleaved by the membrane-associated a-secretase, which cleaves APP within the Ab domain and secretes the aminoterminal portion of APP (APP s ). This p...

BackgroundWhole-exome sequencing (WES) has been successful in identifying genes that cause familial Parkinson’s disease (PD). However, until now this approach has not been deployed to study large cohorts of unrelated participants. To discover rare PD susceptibility variants, we performed WES in 1148 unrelated cases and 503 control participants. Candidate genes were subsequently validated for functions relevant to PD based on parallel RNA-interference (RNAi) screens in human cell culture and Drosophila and C. elegans models.ResultsAssuming autosomal recessive inheritance, we identify 27 genes that have homozygous or compound heterozygous loss-of-function variants in PD cases. Definitive replication and confirmation of these findings were hindered by potential heterogeneity and by the rarity of the implicated alleles. We therefore looked for potential genetic interactions with established PD mechanisms. Following RNAi-mediated knockdown, 15 of the genes modulated mitochondrial dynamics in human neuronal cultures and four candidates enhanced α-synuclein-induced neurodegeneration in Drosophila. Based on complementary analyses in independent human datasets, five functionally validated genes—GPATCH2L, UHRF1BP1L, PTPRH, ARSB, and VPS13C—also showed evidence consistent with genetic replication.ConclusionsBy integrating human genetic and functional evidence, we identify several PD susceptibility gene candidates for further investigation. Our approach highlights a powerful experimental strategy with broad applicability for future studies of disorders with complex genetic etiologies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1147-9) contains supplementary material, which is available to authorized users.