A Brilliant Record of Research Discovery

The following highlights a few of the major scientific discoveries of the Tanz CRND. These include the following categories:

  1. Alzheimer’s Disease
  2. Prions
  3. Parkinson’s disease
  4. Progressive Supranuclear Palsy
  5. Amyotrophic Lateral Sclerosis
  6. Frontotemporal Dementia
  7. Model Organisms
  8. Novel Methodology
  9. Translation And Candidate Therapies


A) Identification of Apolipoprotein E as a major risk factor for late-onset neurodegenerative disorders

In collaboration with Allen Roses the Tanz CRND discovered that APOE ε4 was associated with increased risk for late onset AD (LOAD). This was the first gene for LOAD, and is the strongest known risk factor. APOE genotype is routinely used to partition participants in clinical research and in drug trials. This paper has been cited over 3190 times.

B) The presenilin genes and identification of a novel type of enzyme producing neurotoxic Aβ

Cloning of the presenilin genes opened a new area of biology (intramembranous proteolysis by membrane bound aspartyl proteases) that was not previously recognized and provided conclusive evidence that the accumulation of Aβ was a significant component in the pathobiology of AD. The papers describing the cloning and biological function of PS1 and PS2 have been cited 3966 times.

i) Presenilin 1 (PS1) gene was cloned by the Tanz CRND team using a “positional cloning” strategy. Mutations in PS1 are the principal cause of early onset Familial AD. This work had profound effect on the field, leading to multiple subsequent discoveries including that PS1 was a component of an unusual protein complex that served as a protease that cleaved the transmembrane domains of substrate proteins and that mutations altered the cleavage of APP, causing relative over-expression of longer, neurotoxic Aβ species, thereby confirming a causal role for Aβ accumulation in the pathogenesis of AD. It has also been deployed as a diagnostic test and as a target for therapy (see below).

ii) Cloning of the Presenilin 2 (PS2) gene and documentation that it too was the site of missense mutations in two different unrelated families provided strong biological proof that the presenilin family of proteins was involved in the pathogenesis of AD. The discovery of this homologue also permitted identification of key conserved residues within the two proteins that were critical to its biological function and which, when mutated, both gave rise to AD. The PS2 gene has also been found to be a site for mutations causing some cases of familial late onset Alzheimer’s disease.

iii) Discovery of the effects of presenilin mutations on gamma-secretase-mediated Aβ production.

In collaboration with the group of Dennis Selkoe, we demonstrated that missense mutations in the PS1 gene were associated with alterations in gamma-secretase mediated Aβ production with the relative overproduction of longer Aβ42 species. This work led to 941 direct citations

iv) Identification of other key components of the presenilin complex.

We led the discovery that the presenilin proteins functioned within the context of a high molecular weight membrane-bound protein complex. We identified the first of these components, nicastrin, and went on to demonstrate that nicastrin likely has some role in substrate binding. The description of nicastrin, and subsequent companion work showing a role in substrate binding led to 761 direct citations.

C) Other New Genes for Alzheimer Disease:

A large body of work done by the Tanz CRND and our collaborator led to the discovery of new genes. Most of these genes are associated with the more common late onset forms of AD. This work has been cited over 1111 times.

i) Discovery of SORL1: a new gene for late onset Alzheimer's disease

Discovery of SORL1 as a risk factor for late onset AD. This work, which combined case:control association genetic studies with cell biology and biochemistry, revealed that common variants in the SORL1 gene were associated with increased risk for AD in several different ethnic groups. Additionally, this work confirmed that, as with early onset AD, variation in the handling of APP and its proteolytic products such as Aβ played a role in modulated risk for late onset AD. This paper has generated more than 638 direct citations

ii) Using GWAS for identification of multiple additional genes associated with late onset forms of AD 2010-2014

In total, genome-wide association studies (GWAS) identified 23 genes associated with risk for late onset AD. As part of an international collaboration that collectively assembled more than 60,000 cases and controls we identified 11 new genes associated with risk for late onset AD. Systems biology analyses of the genes thrown up by these GWAS studies suggests that in addition to processes involved in Aβ and APP metabolism, genes involved in cholesterol metabolism, innate immune and inflammation function and intracellular vesicular transport may play key roles in modulating risk for AD. This work led to 651 direct citations.

iii) Discovery of new genes causing Alzheimer's disease by whole exome sequencing

Whole exome sequence studies revealed the presence of rare, moderate effect size mutations in TREM2 and PLD3. As part of a small collaboration that was at the vanguard of applying Whole Exome Sequencing methods to investigate familial cases of AD for rare missense mutations, we identified mutations in TREM2 and PLD3. This work validated the concept that there were mutations that: 1) were too rare to be identified by GWAS studies; and 2) that segregated in families that were too small to be investigated using conventional linkage methods, but which were nevertheless powerfully associated with risk for neurodegenerative disease. The TREM2 discovery correlated well with results from the GWAS studies indicating that alterations in immune innate function were central processes in the pathogenesis of AD. This work led to 169 Citations.

D) Functional Neurobiology of AD

A large body of work has focused on the functional neurobiology of AD. We can highlight only a few examples here. However, these four very recent (<15 years) examples have already been cited 100 times.

i) Discovery that presynaptic alpha2-adrenergic receptor antagonism inhibits the disease progression in an AD-mouse model.

We discovered early depletion in noradrenaline content within the cortex and hippocampus of the TgCRND8 brain.  These reductions were associated with loss of episodic memory, behavioural despair, decreased noradrenergic tone, changes in mitochondrial complex I activity and decreases in BDNF expression.  We found that blocking inhibitory autoceptors with dexofaroxan (Laboratoires Pierre Fabre) reversed the behavioural impairments and restored noradrenergic tone, BDNF levels, and mitochondrial oxidative phosphorylation in the brain (J Neurosci, 2009; Neurobiol Aging, 2012; Neuropsychopharmacol, 2012;  J Alzheimer’s Disease 2014).  Subsequent phase II clinical trials with the alpha2c-adrenergic receptor antagonist, ORM-12741 (Orion Pharma), have now demonstrated significant improvements in episodic memory and working memory, as well as caregiver distress in 100 AD patients.

ii) Discovery of distinct “strains” of Aβ aggregates in Alzheimer’s disease patients. 2013

Mounting evidence contends that aggregates of the Aβ peptide become self-propagating and participate in the pathogenesis of Alzheimer’s disease. We found that distinct “strains” of self-propagating Aβ aggregates can be discerned in the brains of patients with different genetic forms of Alzheimer’s disease, providing further evidence of the prion-like nature of Aβ. These results have provided a potential explanation for the clinical and pathological heterogeneity observed in Alzheimer’s disease. More importantly, heterogeneity in Aβ aggregate conformations suggests that passive Aβ immunotherapy approaches for treating Alzheimer’s disease may only work for certain strains of Aβ. This paper was highlighted in a recent News and Views article in Nature and has led to two direct citations.


E) Interactions of mutated or aggregated AD proteins

i) First in-depth analysis of binders to the tau protein (2015)

Tanz scientists revealed a robust association of tau with the ribonucleoproteome, including major protein complexes involved in RNA processing and translation, and documented binding of tau to several heat shock proteins, the proteasome and microtubule-associated proteins. Follow-up experiments determined the relative contribution of cellular RNA to the tau interactome and mapped interactions to N- or C-terminal tau domains. We further documented that P301L mutant tau disrupts critical interactions of the C-terminal half of tau with heat shock proteins and the proteasome.The data are consistent with a model whereby a higher propensity of P301L mutant tau to aggregate may reflect a perturbation of its chaperone-assisted stabilization and proteasome-dependent degradation. This work was published in Molecular and Cellular Proteomics.

ii) Discovery of a natural small molecule interactor of Aβ that can prevent its amyloid formation (2017)

It is increasingly understood that the appearance of smaller and particularly toxic Aβ clumps represent early signs of AD. To understand how the formation of these smaller Aβ clumps, which are often referred to as oligomeric Aβ (oAβ), triggers other aspects of the disease, we sought to systematically identify molecules in the human brain that oAβ binds to. Amongst more than a hundred human brain proteins that we discovered to bind to Aβ, one of them, a small brain molecule, known as somatostatin (SST), exhibits exquisite selectivity for only binding to oAβ. When we investigated if SST affects the formation of the larger Aβ amyloid deposits, a phenomenon that can be reproduced in the test tube, we noticed that in the presence of SST the appearance of smaller oAβ clumps was favored. We hope that we can harness binding characteristics of SST towards oAβ for the detection of abnormal oAβ in the brain or body fluids of AD patients. If it turns out that the presence of SST in the brain favours the formation of smaller, toxic oAβ clumps over large innocuous Aβ deposits, a new disease intervention strategy could aim to reduce oAβ levels by competing with detrimental aspects of the SST-Aβ interaction. This work was published in 2017 in eLife.



A lot of work has focused on prions proteins. This was not just because of CJD and Mad Cow Disease, but also because valuable lessons could be learned about “spreading” of protein aggregates in these diseases. Listed below is a selection of papers that have been cited over 1439 times.

A) Defining the function of prions: demonstration that the prion protein binds copper in vivo. In collaboration with Hans Kretzschmar, the Tanz CRND demonstrated that unstructured amino-terminal domain of the prion protein binds copper and that membranes prepared from the brains of PrP knockout mice exhibit severe reductions in copper content. This work provided novel insight into the physiological function of the properly folded, cellular isoform of the prion protein.

B) Identification of the prion protein family member Doppel

The Tanz CRND team made the surprising discovery that there is a second member of the prion protein family, which we termed Doppel. Doppel is located immediately downstream of the PrP gene and causes neurodegeneration when expressed ectopically in the brain, but only when PrP is absent. Doppel is routinely used as a tool for investigating the physiological function of the prion protein.

C) First characterization of the prion protein paralog Shadoo

The Tanz CRND team was the first to provide evidence for the existence of Shadoo protein, the third member of the prion protein family. Like PrP, Shadoo exhibits neuroprotective properties and its levels are strikingly reduced in the brain during prion disease. This observation is currently being exploited to determine how prions damage the brain.

D) Discovery of the evolutionary descent of prion proteins from the ZIP family of metal ion transporters. The Tanz CRND team made the surprising discovery that members of the prion protein family are phylogenetically related to a large family of proteins involved in the transport of metal ions across the cellular membrane. In addition to helping explain the existence of the prion protein family, this finding has provided evidence that PrP may be intricately involved in the regulation of cellular zinc ions.

E) Developing a novel model for prion disease

We demonstrated that transgenic mice expressing PrP from the bank vole (BVPrP) exhibit two remarkable properties: (1) they develop a spontaneous, transmissible neurodegenerative disease that recapitulates all the neuropathological hallmarks of prion disease, demonstrating for the first time that wild-type PrP can spontaneously misfold to form infectious prions in vivo; and (2) like bank voles, they are susceptible to prions derived from many different species, suggesting that BVPrP may constitute a “universal acceptor” for prions. These results demonstrate that BVPrP is inherently prone to adopting misfolded conformations, arguing that BVPrP is a superior substrate for probing the biology of prions. This work was highlighted in an article in Science News magazine.


F) Deciphering the physiological role of the prion protein

It is generally assumed that in prion diseases PrP may cause cells to die because the protein acquires an abnormal shape that either does not allow it to fulfill its normal function or causes aberrant interactions with other molecules. Despite being of immense interest, this line of research has been hampered by a lack of insight into the normal role of PrP. We recently discovered that the normal prion protein is critical for a cellular program that is activated when cells are on the move. The latter happens during early embryonic development when cells need to seek their place in the growing body but also is important at specific times in adult tissues, for example, when new neurons or blood cells are formed in the brain or bone marrow, respectively. More specifically, we demonstrated that PrP controls cellular signals that cause the attachment of a negatively charged chain of sugars (polysialic acids) to a specific protein embedded in the cellular membrane (the neural cell adhesion molecule). Once attached to the cell surface, the charge concentration conferred by this sugar chain acts as a repellent (akin to magnets of equal polarity repelling each other) that allows cells to glide along each other.


A) New genes for Parkinson Disease

i) Discovery of PINK1 as a novel cause of Parkinson's disease

We and others identified PINK1 as a novel Parkinson Disease gene (Archiv. Neurology. 61:1898-904) that was subsequently found to be a key regulator of mitochondrial health and cell death pathways.

ii) Glucocerebrosidase A is an important risk factor for PD and DLB.

This collaborative work done by a consortium in which Tanz CRND was involved, provided a new insight into the role of GBA in Lewy body pathology. This work led to 106 direct citations.

B) Biology of PD

The Tanz CRND has also focused research on the biological mechanisms underlying the PD genes. Cumulatively, this work has led to 630 citations.

i) Biology of PINK1. We showed that PINK1 prevents neuronal apoptosis, and that its protective effect is impaired by Parkinson disease-associated mutations neurons in patients with PINK1 mutations. Generally considered a mitochondrial kinase, we characterized a protective cytoplasmic function of PINK1 that requires active kinase function and which regulates mitochondrial fission/fusion machinery. In addition, PINK1 regulates mitophagy, a protein degradation pathway important for mitochondrial turnover and a potential target for PD therapeutics. This work led to 630 direct citations.

ii) A change in α-synuclein solubility and structure is a primary feature of PD and other synucleinopathies, and critical to the prion-like interneuronal propagation of α-synuclein pathology. We have characterized α-synuclein membrane binding and the mechanisms controlling exchange between soluble and membrane compartments, and showed that dissociation of membrane-bound α-synuclein is controlled by brain-specific cytosolic proteins and two PD-linked mutations (A30P and A53T) significantly increase the cytosol-dependent α-synuclein off-rate. These results reveal that cytosolic brain proteins, such as Hsp90, modulate α-synuclein interactions with intracellular membranes and likely participate in pathogenesis. We also identified a cytosolic lipid (platelet activating factor) necessary for α-synuclein binding to synaptic membranes, and the role of pathological pSer129 modification of α-synuclein in membrane binding and turnover, and its upregulation by polo-like kinase 2 and proteasome inhibition. This work led to 517 direct citations.

iii) Identification of a novel protein complex comprising the PD protein α-synuclein and Rab3a, a small GTPase associated with synaptic vesicles, along with Rab GDP-dissociation inhibitor (GDI) and heat shock protein 90 (Hsp90). Importantly, this work revealed how the multimeric complex regulates α-synuclein membrane binding and dissociation. We showed that GTP-bound Rab3a recruits and stabilizes α-synuclein onto vesicle membranes. Following activation of Rab3a GTPase by neuronal depolarization, the GDI/Hsp90 complex induces Rab3a and α-synuclein dissociation from synaptic vesicles (JBC 288:7438, 2013). This work led to 6 direct citations.

iv) Demonstration that the brains of multiple system atrophy patients contain self-propagating α-synuclein aggregates                                                                        Increasing evidence argues that self-propagating protein aggregates feature in the human synucleinopathies, including multiple system atrophy (MSA). We demonstrated that mice expressing mutant α-synuclein develop clinical, biochemical, and pathological signs of a neurodegenerative disease following inoculation with brain extract from MSA patients, indicating that MSA is transmissible. This suggests that MSA is caused a rapidly progressive “strain” of prion-like α-synuclein aggregates. Thus, MSA prions represent the second human prion to demonstrate lethality upon transmission to animals, and the first since kuru prions composed of misfolded prion protein were transmitted to chimpanzees nearly 5 decades ago. Our data also suggest that caution should be exercised when reusing neurosurgical instruments that have been previously used on suspected cases of MSA in order to minimize any risk of iatrogenic transmission of the disease. This work led to 13 direct citations.



A) Identification of common genetic variants influencing risk of  Progressive Supranuclear Palsy                                                                                                           Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10(-3). We found significant previously unidentified signals (P < 5 × 10(-8)) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component. This work led to 89 direct citations.


Sentinel Discoveries in ALS 2003-2014

A. Discovery of abnormal splicing of the neuronal intermediate filament protein, peripherin, in ALS.

We, and others, have shown that the neuronal intermediate protein peripherin is a component of the pathological inclusions characteristic of ALS. We were the first to demonstrate that peripherin pathology is associated with abnormal alternative splicing of peripherin both in mutant SOD1 transgenic mouse models (Per 61) and in ALS (Per 28). We have discovered that the profile of peripherin splice variants can provide a molecular signature of disease and that this could be used in disease stratification. This was one of the earliest studies reporting abnormal splicing in ALS, occurring prior to the discovery of TDP-43, FUS and C9orf72, where defects of RNA metabolism are now considered a key pathological mechanism in ALS. More recently we have identified role(s) for peripherin in vesicle trafficking, perturbations of which could contribute to disease pathogenesis. This work led to 164 direct citations.

B. Identification of monomer/misfolded SOD1 as a therapeutic target for the treatment of ALS.

We were the first to identify and characterize a misfolded form of SOD1 in ALS. The SOD1-Exposed Dimer Interface (SEDI) epitope is exposed only in pathologically, misfolded SOD1 and can be detected in disease tissues using a specific antibody that we generated. Therapeutic targeting of this epitope by active immunization of the SEDI peptide confers neuroprotection in mutant SOD1 transgenic mice, and is currently being tested as a therapeutic in canine degenerating myelopathy, a spontaneously occurring form of ‘ALS’ in dogs. This work led to 290 direct citations.


We have played a role in the discovery and characterization of many of the genes/proteins involved in FTD, including tau, LRRK2, TDP43, FUS, progranulin, etc. Here we highlight our work on the most recently discovered and most prevalent gene – C9ORF72. This work has been cited 731 times.

A) Identification of the C9ORF72 gene

In collaboration with other groups we discovered that the G4C2-expansion in the C9orf72 gene is the most common known cause of both ALS and FTD. It accounts for up to 37% familial and 7% sporadic cases in Caucasians.

B) Discovery of potential disease mechanisms for C9orf72 diseases.

Our studies demonstrated that hypermethylation of the CpG-island is expansion-specific, but not syndrome-specific (ALS vs. FTD). We revealed that a higher degree of methylation was significantly associated with familial cases and shorter disease duration.


The Tanz CRND has contributed novel and widely used models of neurodegenerative disease. These models have been used to help understand causes and mechanisms of disease. They have also been used to test novel candidate therapies. The models have been widely distributed to other academic groups, biotech and pharma companies. Papers first describing the models and their uses have been cited over 1769 times.

A) The TgCRND8 transgenic mouse model of AD.

The TgCRND8 mouse line which was built by overexpression of human APP bearing a double mutation, both of which were associated with human early onset FAD, has provided a highly useful model of the brain amyloid accumulation associated with AD. This mouse has been used both in basic academic science and well as in preclinical therapeutic studies in the hands of academic, biotech and pharmaceutical companies. It has been a principal tool in at least 165 academic papers, including papers describing novel therapeutic approaches published in frontline journals such as Nature, Nature Medicine, PNAS and The Journal of Clinical Investigation. It also has 21000 hits on Google. This work led to 1598 direct citations.

B) The TgTau P301L and TgTau R306W Tg tau transgenic mice have also been widely distributed and used to study tau biology in TFD-Tau and in PSP. Cited 143 times.

C) The FUS and TDP43 C. elegans model of FTD and ALS.

C. elegans models of ALS and FTD have also been widely used to uncover disease mechanisms and potential therapies.


A key ingredient in the work of the Tanz CRND has been our success in inventing and applying novel techniques, methods and instruments. Listed here are a few examples that together have been cited 377 times.  

A) Development of Novel approaches for studying protein protein interactions in living brain

We developed a method that stabilizes existing protein-protein interactions in complex tissues prior to the disruption of tissue integrity. The method, termed time-controlled transcardiac perfusion crosslinking (tcTPC), overcame a notorious Catch-22 in the study of protein interactions involving membrane proteins, where frequently the addition of detergents, required for the solubilization of these proteins, disrupts the very interactions one wants to elucidate. This method has been successfully applied by us and others to investigate the molecular environment of dozens of membrane proteins. The original paper has sporned the appearance of several derivative methods in the literature.

B) Mass spectrometry, Proteomics and neurodegenerative diseases 2000-2014

By using quantitative mass spectrometry, members of the Tanz CRND have generated in-depth inventories of the molecular environments of several key AD proteins, including the amyloid precursor protein (APP), the γ-secretase complexes and the tau protein. These investigations led to the initial discovery of a direct interaction between the amyloid precursor protein (APP) and PrP, established a strong influence of transmembrane protein 21 (TMP21) and leucine-rich repeat and Ig domain containing 1 (LINGO-1) on the proteolytic processing of APP, and uncovered proteins that bind selectively to individual presenilin paralogs encoded in the human genome. This information has shed light on the physiological functions of these proteins and implied new molecular targets for treating neurodegenerative diseases. These technological papers have been cited over 500 times.



The key long term goal of the Tanz CRND has always been to develop novel candidate therapies for neurodegenerative disease. Such candidate therapies may proceed into clinical trials like the two examples described here. Others though are more important because of their ability to describe ideas that may work (with optimized compounds) or are unlikely to work. The latter (negative results) are hugely important because they avoid wasting time and money on clinical trials that have little chance of success and may be dangerous. The examples described here have been cited at least 1598 times.

A) Developing candidate therapies for AD: Anti-Aβ antibodies reduce both Aβ pathology and cognitive impairment.

This work demonstrated that, in addition to clearing the neuropathological features of AD, anti-Aβ antibodies were also capable of preventing the onset of cognitive impairment when given in a preventative paradigm prior to the onset of cognitive impairment and could reverse synaptic loss and cognitive impairment when given after the onset of cognitive impairment in the TgCRND8 mouse model. This work confirmed a pathogenic role for Aβ accumulation and served as initial preclinical proof of principle of clinical trials of anti-Aβ antibodies in humans. The subsequent human studies have led to unclear conclusions because of defects in study design. Thus, some studies have suggested a small effect in anti-Aβ antibody therapy while other studies have shown no statistical effect. Trials are still ongoing, including preventative trials in individuals genetically at risk for AD. The mouse data generated on TgCRND8 more strongly suggests that a preventative immunotherapy approach might be more effective than a secondary treatment approach. This work led to 1398 direct citations.

B) Discovery novel candidate small molecule inhibitors of Aβ aggregation

This work capitalized on an extensive background of work on Aβ oligomerization and neurotoxicity. This work has suggested that some small molecular compounds such as scyllo-inositol were capable of inhibiting assembly of Aβ into neurotoxic oligomers. An illustration of scyllo-inositol as a tool compound confirmed that when given either prophylactically or as a post-onset treatment this compound was capable of reducing/delaying cognitive impairment and synaptic loss in the TgCRND8 model. The compound was taken into human clinical trials but these had to be discontinued because of toxicity at the highest dose. However, the proof of principle that remains of inhibition of oligomer formation by small molecules may be an effective preventative strategy if compounds with the right pharmacokinetics access to the CNS and toxicity profile can be generated. This work led to 200 direct citations.