SearchThe research of the Nixon laboratory focuses on two aspects of neurobiology that govern the fate of normal and pathogenic proteins: the regulation of proteolytic processing and the control of protein export into axons and synapses.
We have identified dysfunction of the endosomal-lysosomal system, involving altered endocytosis and mistrafficking of proteases to endosomes, as the earliest known pathological response of neurons in Alzheimer’s disease.
Our cell modeling studies show early endosomes to be major generators of the toxic β-amyloid peptide and implicate dysfunction of endosomes in the mechanism of β-amyloid accumulation in “sporadic” Alzheimer’s, the most common form of the disease.
Genetic manipulations of proteolytic systems in mice are being used, together with cell culture models, to determine the consequences of endosomal-lysosomal and calpain system dysfunction on processing of Alzheimer-related proteins, receptor-mediated signal transduction, and neuronal cell death pathways.
To maintain neural circuitry, neurons transport a large proportion of their newly synthesized proteins into axons. The perikaryal accumulation of specific cytoskeletal proteins – a pathological hallmark of Alzheimer’s, ALS, and other neurologic diseases – is believed to arise in part from impaired axonal transport.
A second interest of our research is to identify the molecular determinants of cytoskeletal protein transport and assembly in neurons. For example, we are defining the minimum structural requirements for neurofilament translocation by studying axonal transport and axon ultrastructure in mice after targeted deletion or mutagenesis of each of the three neurofilament subunit genes. Neurofilament transport is also regulated by sequential protein phosphorylation, triggered in part by signals from oligodendroglial cells.
We have been determining the signaling pathways, phosphorylation sites, and functional implications of these post-translational modifications. Disease relevance is also being explored in several behavioral and psychiatric settings.
Selected Publications
- Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, Chan H, Bouchet-Marquis C, Bleiwas C, Berg MJ, Huo C, Peddy J, Pawlik M, Levy E, Rao M, Staufenbiel M, Nixon RA. Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022 Jun;25(6):688-701. doi: 10.1038/s41593-022-01084-8. Epub 2022 Jun 2. PMID: 35654956; PMCID: PMC9174056.
- Jiang Y, Alam JJ, Gomperts SN, Maruff P, Lemstra AW, Germann UA, Stavrides PH, Darji S, Malampati S, Peddy J, Bleiwas C, Pawlik M, Pensalfini A, Yang DS, Subbanna S, Basavarajappa BS, Smiley JF, Gardner A, Blackburn K, Chu HM, Prins ND, Teunissen CE, Harrison JE, Scheltens P, Nixon RA. Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration. Nat Commun. 2022 Sep 21;13(1):5308. doi: 10.1038/s41467-022-32944-3. PMID: 36130946; PMCID: PMC9492778.
- Lie PPY, Yoo L, Goulbourne CN, Berg MJ, Stavrides P, Huo C, Lee JH, Nixon RA. Axonal transport of late endosomes and amphisomes is selectively modulated by local Ca2+ efflux and disrupted by PSEN1 loss of function. Sci Adv. 2022 Apr 29;8(17):eabj5716. doi: 10.1126/sciadv.abj5716. Epub 2022 Apr 29. PMID: 35486730; PMCID: PMC9054012.
- Pensalfini A, Kim S, Subbanna S, Bleiwas C, Goulbourne CN, Stavrides PH, Jiang Y, Lee JH, Darji S, Pawlik M, Huo C, Peddy J, Berg MJ, Smiley JF, Basavarajappa BS, Nixon RA. Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease. Cell Rep. 2020 Nov 24;33(8):108420. doi: 10.1016/j.celrep.2020.108420. PMID: 33238112; PMCID: PMC7714675.