Advances in Research

Date Milestone Details
March 2008

Tanz Centre scientists link alterations in serotonin turnover to specific affective phenotypes in a mouse model of Williams' syndrome.

2008 - 2012

Tanz Centre researchers generate quantitative protein-protein interaction maps of key molecules known to be intimately involved in the etiology of Alzheimer’s disease. They perform the first large-scale quantitative and comparative interactome studies of the amyloid precursor protein (APP) and of distinct gamma-secretase complexes known to be critical for the cleavage of APP and other substrates. The studies uncovered an influence of the protein LINGO-1on the proteolytic processing of APP, consolidated similarities in the biology of APP and a related membrane protein referred to as p75 and revealed that PS1 and PS2 components of gamma-secretase complexes may divide up the task of handling a broad range of membrane protein substrates at least in part by associating with different molecular environments.

2008

Tanz Centre scientists show that there is abnormal splicing of the neuronal intermediate filament protein, peripherin, in Amyotrophic Lateral Sclerosis, generating a truncated isoform called Per 28.

Tanz Centre scientists begin three studies that will show that the PD gene PINK1 mitigates neuronal death and regulates mitochondrial fission-fusion and turnover, which are now recognized as key pathways in Parkinson disease.
 

September 2007

Tanz Centre scientists demonstrate that the SPRN gene encodes a CNS expressed protein “shadoo” with biochemical resemblance to PrP. In functional assays in cerebellar neurons the protein has PrP-like protective activity against delta PrP or the Doppel protein. Most remarkably, steady state levels of the shadoo protein are markedly reduced in prion-infected animals. A simple hypothesis is that clinical target areas in prion disease reflect loss of shadoo’s protective action.

June 2007

Tanz Centre researchers develop the first antibody that specifically labels misfolded superoxide dismutase-1 (SOD1). Mutations in SOD1 are the only known cause of amyotrophic lateral sclerosis (ALS). The antibody has potential utility for use in biomarker studies, drug discovery and development of immunization strategies for the treatment of ALS caused by mutations in SOD1.

The researchers show that mutant SOD1 transgenic mice lack abnormalities of the TAR DNA Binding Protein (TDP-43).

They demonstrate through identification of a unique pathological epitope that superoxide dismutase-1 (SOD1) is misfolded in transgenic mice expressing mutant forms of SOD1 related to Amyotrophic Lateral Sclerosis
 

February 2007

Tanz Centre scientists report that inherited variants in the neuronal sorting receptor, SORL1, are associated with late-onset Alzheimer’s disease in different ethnic groups. This study emphasizes the complexity of the genetics of the common late-onset form of Alzheimer’s disease. The study included multiple Centers and tested ~7,000 DNA samples from Caucasians, Hispanics, Arab Israelis and African Americans and uncovered two consistent patterns that linked the SORL1 gene to AD. These AD-associated variants may down-regulate tissue-specific expression of SORL1. They also show that SORL1 directs trafficking of APP into recycling pathways, and that when SORL1 is under-expressed, APP is sorted into Aβ-generating compartments. Hence, the inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing common late-onset form of Alzheimer’s disease.

December 2006

The Tanz Centre becomes the first to identify FTD-causing mutations in the IFT74 gene on chromosome 9.

November 2006

Tanz Centre scientists discover that Corticobasal Degeneration can be caused by mutations in the progranulin gene.

October 2006

Tanz Centre researchers identify regulation of α-synuclein solubility in neurons by specific brain proteins, a process that is disrupted by PD-linked mutations in α-synuclein. Identification of these factors has implications for understanding PD pathogenesis.

October 2006

Tanz Centre scientists generate a robust transgenic mouse model of disorders such as FTD, AD, and PSP, in which the tau protein accumulates inside brain cells, and leads to neurodegeneration. The tau protein is the principal component of neurofibrillary tangles. This mouse model will help scientists understand why the tau protein aggregates into neurotoxic intracellular inclusions, and how this causes neurodegeneration.

July 2006

Tanz Centre researchers discover that scyllo-inositol can inhibit the accumulation of Aβ into small neurotoxic aggregates (termed “oligomers”) and block many of the features of AD in mouse models of this disease. These two observations led to the initiation of human clinical trials of scyllo-inositol in patients with AD.

2006

Tanz Centre scientists begin a study that characterizes the regulation of α-synuclein membrane binding. α-Syn is both a genetic cause and a pathological marker of PD, and detergent-insoluble deposits of biochemically modified and misfolded α-syn are a consistent feature of sporadic and genetic forms of PD. They reveal a novel mechanism by which brain cytosolic proteins and specific lipids modulate α-synuclein interactions with intracellular membranes.

October 2005

Tanz Centre scientists identify the protective role of PINK1 protein to suppress neuronal death and loss-of-function effects induced by PD-linked mutations.

June 2005

Tanz researchers demonstrate that although the presenilin protein (PS1 and PS2) components of γ-secretase complexes have similar amino acid sequences, they have very different biochemical properties and different functions. This is turning out to be important for the development of drugs which selectively inhibit the role of these proteins in the generation of neurotoxic Aβ by the γ-secretase enzyme.

December 2004

Tanz Centre scientists invent a cellular assay for the prion protein protective effect.

March 2003

Tanz Centre researchers show that there is deregulated expression of alternatively-spliced variants of the peripherin protein in ALS, and that these may play a role in the neurodegenerative process.

December 2001, December 2004

Tanz Centre researchers define the antagonistic activities of PrP and Doppel in Tg mice.

December 2000

Drs Peter St George-Hyslop, David Westaway and Chris Janus generate a powerful transgenic mouse model of Alzheimer’s disease and show that vaccination of this mouse with Aβ has dramatic effects on memory and brain pathology. This work shows that Aβ vaccination (and other therapies which block or inhibit Aβ) might be used to treat Alzheimer's disease.

December 2000, November 2002

Tanz Centre researchers make two important findings: the discovery that antibodies to Aβ can block cognitive decline in mouse models of AD, and the discovery of the precise part of Aβ that these antibodies must bind to in order to block AD. These two discoveries encourage the use of immune (active or passive vaccine-based) therapies for AD in humans, and the refinement of these immune therapies to avoid induction of allergic encephalitis (an occasional complication of vaccination with the full-length Aβ-peptide).

July 2000

Drs Peter St George-Hyslop and Paul Fraser discover a new gene, Nicastrin, involved in the biochemical processes leading to Alzheimer neurodegeneration.

Pages