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Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.

ABSTRACT: Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to prevent the endoplasmic reticulum (ER)-resident chaperone, cyclophilin B, from assisting presenilin 1 to fold properly, leading to its aggregation, deposition in the ER, reduction of ?-secretase activity, and impaired mitochondrial distribution and function. Similarly, reduced quantities of the processed, active presenilin 1 were observed in brains of cyclophilin B knockout mice. These discoveries imply that reduced cyclophilin activity contributes to the development of distinct neurodegenerative disorders, propose a novel mechanism for the development of certain fAD cases, and support the emerging theme that this disorder can stem from aberrant presenilin 1 function. This study also points at ER chaperones as targets for the development of counter-neurodegeneration therapies.

SUBMITTER: Ben-Gedalya T

PROVIDER: S-EPMC4682640 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.

Ben-Gedalya Tziona T Moll Lorna L Bejerano-Sagie Michal M Frere Samuel S Cabral Wayne A WA Friedmann-Morvinski Dinorah D Slutsky Inna I Burstyn-Cohen Tal T Marini Joan C JC Cohen Ehud E

The EMBO journal 20151005 22

Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to the manifestation of distinct neurodegenerative disorders and identified similar neurodegeneration-linked proline substitutions in the prion protein and in presenilin 1 that underlie the development of a prion disorder and of familial Alzheimer's disease (fAD), respectively. These substitutions were found to pr ...[more]

PMID: 26438723

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Project description:Mitochondrial dysfunction and oxidative stress are frequently observed in the early stages of Alzheimer's disease (AD). Studies have shown that presenilin-1 (PS1), the catalytic subunit of γ-secretase whose mutation is linked to familial AD (FAD), localizes to the mitochondrial membrane and regulates its homeostasis. Thus, we investigated how five PS1 mutations (A431E, E280A, H163R, M146V, and Δexon9) observed in FAD affect mitochondrial functions. Methods: We used H4 glioblastoma cell lines genetically engineered to inducibly express either the wild-type PS1 or one of the five PS1 mutants in order to examine mitochondrial morphology, dynamics, membrane potential, ATP production, mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), oxidative stress, and bioenergetics. Furthermore, we used brains of PS1M146V knock-in mice, 3xTg-AD mice, and human AD patients in order to investigate the role of PS1 in regulating MAMs formation. Results: Each PS1 mutant exhibited slightly different mitochondrial dysfunction. Δexon9 mutant induced mitochondrial fragmentation while A431E, E280A, H163R, and M146V mutants increased MAMs formation. A431E, E280A, M146V, and Δexon9 mutants also induced mitochondrial ROS production. A431E mutant impaired both complex I and peroxidase activity while M146V mutant only impaired peroxidase activity. All PS1 mutants compromised mitochondrial membrane potential and cellular ATP levels were reduced by A431E, M146V, and Δexon9 mutants. Through comparative profiling of hippocampal gene expression in PS1M146V knock-in mice, we found that PS1M146V upregulates Atlastin 2 (ATL2) expression level, which increases ER-mitochondria contacts. Down-regulation of ATL2 after PS1 mutant induction rescued abnormally elevated ER-mitochondria interactions back to the normal level. Moreover, ATL2 expression levels were significantly elevated in the brains of 3xTg-AD mice and AD patients. Conclusions: Overall, our findings suggest that each of the five FAD-linked PS1 mutations has a deleterious effect on mitochondrial functions in a variety of ways. The adverse effects of PS1 mutations on mitochondria may contribute to MAMs formation and oxidative stress resulting in an accelerated age of disease onset in people harboring mutant PS1.

Project description:BackgroundIn contrast to sporadic Alzheimer's disease, autosomal dominant Alzheimer's disease (ADAD) is associated with greater neuropathological evidence of cerebellar amyloid plaque (Aβ) deposition. In this study, we used positron emission tomography (PET) measurements of fibrillar Aβ burden to characterize the presence and age at onset of cerebellar Aβ deposition in cognitively unimpaired (CU) Presenilin-1 (PSEN1) E280A mutation carriers from the world's largest extended family with ADAD.Methods18F florbetapir and 11C Pittsburgh compound B (PiB) PET data from two independent studies - API ADAD Colombia Trial (NCT01998841) and Colombia-Boston (COLBOS) longitudinal biomarker study were included. The tracers were selected independently by the respective sponsors prior to the start of each study and used exclusively throughout. Template-based cerebellar Aβ-SUVR (standard-uptake value ratios) using a known-to-be-spared pons reference region (cerebellar SUVR_pons), to a) compare 28-56-year-old CU carriers and non-carriers; b) estimate the age at which cerebellar SUVR_pons began to differ significantly in carrier and non-carrier groups; and c) characterize in carriers associations with age, cortical SUVR_pons, delayed recall memory, and API ADAD composite score.ResultsFlorbetapir and PiB cerebellar SUVR_pons were significantly higher in carriers than non-carriers (p < 0.0001). Cerebellar SUVR_pons began to distinguish carriers from non-carriers at age 34, 10 years before the carriers' estimated age at mild cognitive impairment onset. Florbetapir and PiB cerebellar SUVR_pons in carriers were positively correlated with age (r = 0.44 & 0.69, p < 0.001), cortical SUVR_pons (r = 0.55 & 0.69, p < 0.001), and negatively correlated with delayed recall memory (r = -0.21 & -0.50, p < 0.05, unadjusted for cortical SUVR_pons) and API ADAD composite (r = -0.25, p < 0.01, unadjusted for cortical SUVR_pons in florbetapir API ADAD cohort).ConclusionThis PET study provides evidence of cerebellar Aβ plaque deposition in CU carriers starting about a decade before the clinical onset of ADAD. Additional studies are needed to clarify the impact of using a cerebellar versus pons reference region on the power to detect and track ADAD changes, even in preclinical stages of this disorder.

Project description:Mutations in presenilin 2 are rare causes of early onset familial Alzheimer's disease. Eighteen presenilin 2 mutations have been reported, although not all have been confirmed pathogenic. Much remains to be learned about the range of phenotypes associated with these mutations. We have analysed our unique collection of 146 affected cases in 11 Volga German families, 101 who are likely to have the same N141I mutation in presenilin 2 (54 genotyped confirmed). We have also assessed the detailed neuropathologic findings in 18 autopsies from these families and reviewed the world's literature on other presenilin 2 mutations; presenting a novel mutation that is predicted to lead to a premature truncation codon. Seven presenilin 2 mutations reported in the literature have strong evidence for pathogenicity whereas others may be benign polymorphisms. One hundred and one affected persons, with sufficient historical information from the Volga German pedigrees (N141I mutation), had a mean onset age of 53.7 years+/-7.8 (range 39-75) and mean age at death of 64.2 years+/-9.8 (range 43-88). These figures overlap with and generally fall between the results from the subjects in our centre who have late onset familial Alzheimer's disease or mutations in presenilin 1. Seizures were noted in 20 (30%) of 64 subjects with detailed medical records. Two mutation carriers lived beyond age 80 without developing dementia, representing uncommon examples of decreased penetrance. Two persons had severe amyloid angiopathy and haemorrhagic stroke. Eighteen cases had detailed histopathology available and analysed at our institution. Braak stage was five or six, amyloid angiopathy and neuritic plaques were common and more than 75% had Lewy bodies in the amygdala. TAR DNA-binding protein-43 inclusions were uncommon. In addition, a 58-year-old female with a 2 year course of cognitive decline and no family history of dementia has abnormal fludeoxyglucose-positron emission tomography imaging and a novel 2 base pair deletion in presenilin 2 at nucleotide 342/343, predicted to produce a frame-shift and premature termination. We conclude that mutations in presenilin 2 are rare with only seven being well documented in the literature. The best studied N141I mutation produces an Alzheimer's disease phenotype with a wide range of onset ages overlapping both early and late onset Alzheimer's disease, often associated with seizures, high penetrance and typical Alzheimer's disease neuropathology. A novel premature termination mutation supports loss of function or haploinsufficiency as pathogenic mechanisms in presenilin 2 associated Alzheimer's disease.

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Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.

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Alzheimer's disease-causing proline substitutions lead to presenilin 1 aggregation and malfunction.

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