Advances in Research

Datesort descending Milestone Details
2000 - 2006

Tanz Centre scientists identify several extended families with mutations in the Parkin, DJ-1, PINK1, LRRK2 and GBA genes.

2000-2006

Tanz Centre scientists identify several extended families with mutations in the Parkin, DJ-1, PINK1, LRRK2 and GBA genes.

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.

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.
 

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.

2009

The Centre for Research in Neurodegenerative Diseases is officially renamed The Tanz Centre for Research in Neurodegenerative Diseases

Tanz Centre scientists show, using a novel antibody, SEDI antibody, that superoxide dismutase-1 (SOD1 ) is misfolded in cases of Amyotrophic Lateral Sclerosis caused by mutations in SOD1.
 

2009 - 2011

Tanz Centre researchers discover the evolutionary descent of  prion proteins from a larger family of ZIP metal ion transporters.The prion protein is responsible for a group of fatal neurodegenerative diseases that include Creutzfeldt-Jakob disease (CJD) in humans and Bovine Spongiform Encephalopathy (BSE) in cattle. Work at the institute establishes the evolutionary origin of the prion gene family to be the result of a genomic insertion of a spliced and C-terminally truncated transcript of a ZIP metal ion transporter, thus leading to the proposition that the prion founder gene constituted a retrogene. These data explain the hitherto puzzling characteristics of the prion protein as remnants of an ancient function in the sensing and transport of metal ions.

2010

Tanz Centre scientists develop a new antibody recognizing unfolded SOD1, USOD antibody, and show that inclusions containing TAR DNA Binding Protein (TDP-43) or misfolded SOD1 are non-amyloidogeneic.

2012

Tanz Centre scientists show that immuno-targeting of monomer/misfolded SOD1 may have therapeutic potential for the treatment of Amyotrophic Lateral Sclerosis caused by mutations in SOD1.

2012

Tanz Centre researchers provide the first glimpse into a molecular biology that ties the prion protein to its ZIP transporter molecular cousins and suggests that cellular zinc starvation plays a role in prion disease - evidence that a subset ZIP metal ion transporters which contain a prion protein-like ectodomain can interact with the cellular prion protein and undergo abnormal cleavages in prion disease.

2013

Tanz Centre scientists conducted the first epigenetic study of C9orf72 underlying silencing of C9orf72 expression. It was revealed that DNA hypermethylation of the CpG island 5’ of the repeat is associated with the presence of expansion; and a higher degree of methylation was correlated with shorter disease duration and with familial ALS.

2013 and 2015

The genome-wide study by Tanz CRND scientists revealed that Alzheimer’s disease is linked to recessive inheritance that can be related to the presence of long runs of homozygosity (ROHs). First, we investigated an inbred population of Caribbean Hispanics and obtained evidence that ROHs could be a significant contributor to the etiology of Alzheimer’s disease. For instance, people with Alzheimer’s disease have longer ROHs than controls; a clue that recessive genes are lurking in those parts of the genome [Ghani, et al, JAMA Neurol 2013]. Second, we led the international genetic consortium to conduct ROH-analysis of the largest African American dataset [Ghani, et al, JAMA Neurol, 2015]. This is an essential study, since the risk of Alzheimer’s disease among African Americans is up to three times higher than among Caucasians. The value of our study is in the identification of cases with a higher probability of having rare mutations, which could make the search for mutations cost-efficient.

2015

Tanz CRND scientists revealed that the C9orf72 G4C2 repeat itself is the main site of DNA methylation. By developing a novel assay, they demonstrated that the G4C2-repeat expansion is methylated in carriers of >90 repeats (100%), while the intermediate (22-90 repeats) and small (<22 repeats) alleles are unmethylated. The presence of G4C2-methylation was identified in both blood and brain tissues, implying its use as a biomarker. This study contributed to understanding the consequences of expansion and might help to establish a more accurate cut-off for pathogenic repeat. For instance, our investigation of a large ALS family revealed that a 70-repeat allele from the unaffected father expanded during parent-offspring transmission and started the first generation affected by ALS (four children carry ~1,750-repeats). Epigenetic and RNA-expression analyses further discriminated the large expansions (methylated and associated with reduced C9orf72 expression) from the 70-repeat allele (unmethylated and associated with up-regulation of C9orf72). The small expansions might be considered ‘‘pre-mutations’’ to reflect their propensity to expand in the next generation. These findings support a hypothesis of multiple origins for the expansion; and might help explain the high frequency of sporadic ALS/FTD patients (e.g., 21% among Finnish ALS subjects).

April 2000

Drs JoAnne McLaurin and Paul Fraser discover inositol stereoisomers that inhibit amyloid formation and form complexes that are non-toxic to neurons, the primary targets of destruction in Alzheimer’s disease. This discovery will enable the development of an anti-amyloid drug therapy for Alzheimer’s disease.

April 2012

Tanz Centre scientists demonstrate early and progressive loss of noradrenaline in the TgCRND8 mice. They demonstrate that these deficits coincided with the onset of cortically encoded memory impairment and BDNF dysregulation. They also demonstrate that the neurochemical deficits and the AD-like behaviours could be reversed with a presynaptic alpha-2-adrenergic receptor antagonist that increases noradrenergic and cholinergic transmission.

August 1995

Dr. Peter St George-Hyslop and his team of international scientists discover a second gene (Presenilin 2 - located on chromosome 1) responsible for a less severe form of familial early-onset Alzheimer’s disease.

August 1998

Based upon research into therapeutics by Drs Paul Fraser, Robert Kisilevsky and Francine Gervais, a new drug for the treatment for amyloid plaques enters Phase II trials and is granted FDA approval (April 1999). Related compounds enter Phase 1 for the treatment of Alzheimer’s disease in collaboration with Lundbeck Pharmaceuticals (Copenhagen).

December 1992

Drs Peter St George-Hyslop, Don Crapper McLachlan and others report that chromosome 14 contains a gene (at that time unidentified) which causes the early onset of familial Alzheimer’s Disease.

December 1999

In collaboration with Dr. T. Katayama from Osaka University in Japan, Dr. Peter St George-Hyslop and others show that the presenilin 1 gene is involved in the metabolism of several important proteins, including the β-amyloid precursor protein and a protein involved in the unfolded protein response in the endoplasmic reticulum of cells.

December 1999

Drs D. Grimes, Catherine Bergeron, and Anthony Lang demonstrate that dementia is the most common presentation of corticobasal degeneration.

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