RGD Reference Report - Identification of two novel synaptic ¿-secretase associated proteins that affect amyloid ß-peptide levels without altering Notch processing. - Rat Genome Database

RGD Reference Report - Identification of two novel synaptic ¿-secretase associated proteins that affect amyloid ß-peptide levels without altering Notch processing. - Rat Genome Database

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Identification of two novel synaptic ¿-secretase associated proteins that affect amyloid ß-peptide levels without altering Notch processing.
Authors:	Frykman, Susanne Teranishi, Yasuhiro Hur, Ji-Yeun Sandebring, Anna Yamamoto, Natsuko Goto Ancarcrona, Maria Nishimura, Takeshi Winblad, Bengt Bogdanovic, Nenad Schedin-Weiss, Sophia Kihara, Takahiro Tjernberg, Lars O
Citation:	Frykman S, etal., Neurochem Int. 2012 Jul;61(1):108-18. doi: 10.1016/j.neuint.2012.03.016. Epub 2012 Apr 10.
RGD ID:	13824973
Pubmed:	PMID:22521230 (View Abstract at PubMed)
DOI:	DOI:10.1016/j.neuint.2012.03.016 (Journal Full-text)
Synaptic degeneration is one of the earliest hallmarks of Alzheimer disease (AD) and results in loss of cognitive function. One of the causative agents for the synaptic degeneration is the amyloid ß-peptide (Aß), which is formed from its precursor protein by two sequential cleavages mediated by ß- and γ-secretase. We have earlier shown that γ-secretase activity is enriched in synaptic compartments, suggesting that the synaptotoxic Aß is produced locally. Proteins that interact with γ-secretase at the synapse and regulate the production of Aß can therefore be potential therapeutic targets. We used a recently developed affinity purification approach to identify γ-secretase associated proteins (GSAPs) in synaptic membranes and synaptic vesicles prepared from rat brain. Liquid chromatography-tandem mass spectrometry analysis of the affinity purified samples revealed the known γ-secretase components presenilin-1, nicastrin and Aph-1b along with a number of novel potential GSAPs. To investigate the effect of these GSAPs on APP processing, we performed siRNA experiments to knock down the expression of the GSAPs and measured the Aß levels. Silencing of NADH dehydrogenase [ubiquinone] iron-sulfur protein 7 (NDUFS7) resulted in a decrease in Aß levels whereas silencing of tubulin polymerization promoting protein (TPPP) resulted in an increase in Aß levels. Treatment with γ-secretase inhibitors often results in Notch-related side effects and therefore we also studied the effect of the siRNAs on Notch processing. Interestingly, silencing of TPPP or NDUFS7 did not affect cleavage of Notch. We also studied the expression of TPPP and NDUFS7 in control and AD brain and found NDUFS7 to be highly expressed in vulnerable neurons such as pyramidal neurons in the hippocampus, whereas TPPP was found to accumulate in intraneuronal granules and fibrous structures in hippocampus from AD cases. In summary, we here report on two proteins, TPPP and NDUFS7, which interact with γ-secretase and alter the Aß levels without affecting Notch cleavage.

Cellular Component

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Ndufs7	Rat	synaptic membrane		IDA			RGD

Genes (Rattus norvegicus)


Ndufs7 (NADH:ubiquinone oxidoreductase core subunit S7)