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Suh Lab

The Suh Lab studoes the genetic and molecular mechanism of Alzheimer’s disease and spinocerebellar ataxia, with the aim of identifying novel therapeutic targets and developing effective drugs for patients.

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    Research Overview

    In the Suh Lab, we study the genetic and molecular mechanism of Alzheimer’s disease (AD) and spinocerebellar ataxia (SCA), with the aim of identifying novel therapeutic targets and developing effective drugs for patients. We have two main projects in the lab. The first is to study the role of ADAM10-mediated cleavage of APP in brain physiology and AD pathogenesis. This project is based on our novel hypothesis that goes beyond ADAM10’s well-known function of precluding Aβ generation. The second project is to study the impact of increased BACE1 expression in spinocerebellar ataxia type 1 (SCA1) brains on disease pathogenesis. Primarily, we test if BACE1 inhibitor could be developed as a viable therapeutic for SCA. For these two projects, we generate and/or use genetically modified mouse models that are relevant to the two neurodegenerative diseases.

    The third project in development is to identify genetic factors of highly superior autobiographical memory (HSAM), a neuropsychiatric trait recently identified in about 100 individuals worldwide. Those individuals who have it can recall in great detail what happened on a specific day years and decades ago.

    Project 1: Role of ADAM10-Mediated Cleavage of APP in AD Etiology and Pathogenesis

    Manifestation of Alzheimer’s disease – deterioration of cognitive functions and distinct brain pathologies – is the result of numerous factors’ interplay over decades in the affected individuals. In addition to these, the lack of understanding the underlying mechanism of memory and cognition itself has made it exceptionally challenging to elucidate the disease’s etiology and pathogenesis. Paradoxically, perhaps the only possible route to clarify is to develop effective therapies and medicines. In this regard, among many, the most studied biological pathway and tested hypothesis of AD, which was postulated from the major pathological and genetic evidence, lies around the metabolism of amyloid precursor protein (APP) and its cleavage product amyloid-β (Aβ). Recently, a few drugs aiming to remove Aβ from the brains were approved for AD, but their efficacy and safety still needs to be further validated in patients. The cause of Alzheimer’s disease is still unclear, though aging and genetics are undoubtedly the two greatest risk factors.

    ADAM10 is the major α-secretase in the brain that cleaves APP in the middle of the Aβ sequence and sheds large ectodomain sAPPα from the cell surface (Fig. 1). Beyond precluding Aβ generation, previous studies by others and our recent findings showed that the metalloprotease has a critical role in regulating neuronal adhesion and trans-synaptic interaction via the cleavage of its substrates, including APP. Previously, we have identified two AD-associated mutations in ADAM10 and elucidated their pathogenic mechanism as attenuating α-secretase activity (Suh et al., 2013). In line with this, more recent large-scale genome-wide association studies and whole exome sequencing analysis consistently showed that ADAM10 is strongly associated with AD and loss of ADAM10 function increases AD risk. These findings suggest ADAM10 plays a critical role in AD etiopathogenesis and increasing ADAM10 expression can be a promising therapeutic target.

    Currently, we are studying whether increasing ADAM10 cleavage of APP is a viable therapeutic target for AD. Our hypothesis is mainly based on physiological functions of APP and ADAM10, beyond their evident roles in Aβ generation. We attempt to develop experimental drugs that increase ADAM10 expression selectively in the brain.

    Project 2: BACE1 as Therapeutic Target for Spinocerebellar Ataxia

    BACE1 is a key protease in Alzheimer’s disease (AD) pathogenesis as it cleaves APP and generates amyloid-β (Aβ), the main culprit of senile plaques in AD brain (Fig. 1). For this reason, BACE1 has been a major therapeutic target for AD; however, recent clinical trials of BACE1 inhibitors did not produce a positive outcome for AD patients. While the BACE1 level in a brain with AD is increased distinctively in dystrophic neurites around Aβ plaques, in a healthy brain, BACE1 is detected throughout neurons with a high expression in presynaptic terminals (Fig. 2).

    Beyond mediating the first step in generating Aβ, proteolytic activity of BACE1 is involved in a variety of physiological processes of the nervous system, such as axonal guidance, synaptic plasticity, neuronal excitability, and motor coordination. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease that impairs motor coordination and movement, leading to early mortality. Expansion of CAG trinucleotides repeat encoding a polyglutamine (polyQ) track in ataxin-1 gene (ATXN1) is the genetic determinant of the disease that has no effective therapy yet. In a prior study (Suh et al., 2019 Cell), we demonstrated that loss of ataxin-1 (Atxn1−/−) increases BACE1 transcription selectively in the cerebrum (Fig. 3). The BACE1 increase exacerbated Aβ pathology in mouse models of AD and impaired hippocampal neurogenesis and olfactory axonal targeting. However, in SCA1 mice (Atxn1154Q/+), polyQ-expanded mutant ataxin-1 led to BACE1 increase post-transcriptionally, both in the cerebrum and cerebellum, in a disease progression-dependent manner (Fig. 4).

    These findings led us to hypothesize that increased BACE1 level in SCA1 brain exacerbates the disease progression, and we tested if genetic reduction of BACE1 would ameliorate SCA1 motor deficits and neuropathology. Our findings show that compared to Atxn1154Q/+ littermates, Atxn1154Q/+; Bace1+/− mice perform significantly better in tests measuring locomotive activity, coordination, and explorative activity (PCT publication number: WO 2023/230282). We are currently studying the effects of BACE1 genetic reduction on SCA1 neuropathology and the underlying mechanism of BACE1 increase in SCA1 brains. We plan to test whether BACE1 inhibitor initially developed for AD could be developed as a drug for SCA patients.


    Project 3: Genetic Investigation of Novel Autobiographical Memory

    Searching for therapeutic targets and developing effective drugs for Alzheimer’s disease has so far mostly relied on better understanding of the etiology and pathogenesis of the disease. In this project, we approach from a different angle to achieve the same goal: finding a cure for Alzheimer’s. We attempt to achieve the goal by uncovering the genetic cause of a very rare and unusual ‘ability to not forget.’

    This extraordinary memory was first reported in 2006 by Dr. James McGaugh at University of California at Irvine as he examined a 40-year-old woman, Jill Price (Parker et al., 2006). Strikingly, she demonstrated that she could remember almost all episodes in her life since puberty, in such a detail as if those events had happened just yesterday. Since this report, about 100 individuals have so far been identified worldwide to have the same distinct memory, named ‘highly superior autobiographical memory (HSAM).’ Beyond the autobiographical memory – the recollection of personal episodes and factual knowledge about the world – they do not exhibit superiority in other types of memory, such as remembering the content of a book they read. While some HSAM individuals exhibit obsessive and compulsive behaviors, they otherwise are mostly normal and healthy.

    Although HSAM appears not to be hereditary, it accompanies distinctive characteristics that suggest it has a genetic cause, at least to a certain degree. In collaboration with Unit director Dr. Rudolph Tanzi at MGH, Drs. James McGaugh and Michal Yassa at UC Irvine, and Dr. Eunjung (Alice) Lee at Boston’s Children’s Hospital, we have set hypotheses that could explain the genetics of HSAM and initiated to test them through the DNA sequencing analysis of HSAM individuals and families.

    Lab Members

    Jaehong Suh, PhDJaehong Suh, PhD
    Principal Investigator

    Dr. Jaehong Suh joined the Genetics and Aging Research Unit at Massachusetts General Hospital in 2006 as a postdoctoral Research Fellow. In the Suzanne Guenette lab, he studied the role of FE65 and FE65L1 in APP metabolism in neurons. He also found that loss of the two APP binding proteins causes cataracts and muscle weakness. He then moved to the Rudy Tanzi lab in the Unit and studied in vivo pathogenic mechanisms of ADAM10 mutations found in several late-onset AD families. Dr. Suh then studied the role of ataxin-1 loss of function on BACE1 expression and AD pathogenesis.

    During that time in the Unit, Dr. Suh was promoted to Instructor in 2010 and Assistant Professor of Neurology in 2014. He established his own lab and continues the research to elucidate the underlying mechanisms of AD and SCA, identify viable therapeutic targets, and develop effective drugs for the neurodegenerative diseases. Prior to joining Mass General, he studied neuronal death mechanism and tau splicing changes in ischemic brain as a postdoctoral fellow at Ajou University School of Medicine in South Korea. Dr. Suh received both his B.S. and PhD degrees in Biological Sciences from Korea Advanced Institute of Science and Technology (KAIST). For his PhD thesis, Dr. Suh studied cellular and molecular mechanisms of dioxin and dioxin-like compounds (polychlorinated biphenyls)-induced adverse effects on immune functions. Dr. Suh’s research at Mass General has been supported through grants from the NIH, Cure Alzheimer’s Fund, MassCATS, and BrightFocus Foundation.

    View Dr. Suh's Harvard Catalyst profile

    Recent Publications

    1. Suh J, Choi SH, Romano DM, Gannon MA, Kim DY, Tanzi RE (2013). ADAM10 Missense Mutations Potentiate β-Amyloid Accumulation by Impairing Prodomain Chaperone Function. Neuron, 80, 385-401. PMCID: PMC4105199.
    2. Suh J*, Moncaster JA, Wang L, Hafeez I, Herz J, Tanzi RE, Goldstein LE, Guénette SY* (2015). FE65 and FE65L1 amyloid precursor protein-binding protein compound null mice display adult-onset cataract and muscle weakness. FASEB J, 29, 2628-39. PMCID: PMC4447227. *Corresponding authors.
    3. Suh J*,#, Romano DM, Nitschke L, Herrick SP, Dimarzio BA, Dzhala V, Bae JS, Oram MK, Zheng Y, Hooli B, Mullin K, Gennarino VA, Wasco W, Schmahmann JD, Albers MW, Zoghbi HY*, Tanzi RE* (2019). Loss of Ataxin-1 Potentiates Alzheimer's Pathogenesis by Elevating Cerebral BACE1 Transcription. Cell, 178, 1159-1175. PMCID: PMC6726125. *Corresponding authors. #Lead contact.
    4. Dzhala V*, Fowler AJ, DiMarzio BA, Staley KJ, Suh J*,# (2022) Analysis of brain region-specific mRNA synthesis and stability by utilizing adult mouse brain slice culture. STAR Protoc. 3, 101349. PMCID: PMC9059153. *Corresponding authors. #Lead contact.
    5. Fowler AJ, Tanzi RE, Suh J (2023). Modulation of BACE1 as a Therapy for Spinocerebellar Ataxia. Patent Cooperation Treaty (PCT). International filing date: May 25, 2023. Publication date: November 30, 2023. Publication number: WO 2023/230282.

    Featured News

    Balance Clue? – Harvard Medical School News

    Raw Deal: Lose Ataxin, Gain BACE – AlzForum

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