Welcome to the Cohen lab at UNC-Chapel Hill !
Our mission statement:
One-liner: To identify the pathogenic mechanisms underlying neurodegenerative disease.
More specifically: Although distinct, many of these diseases share common underlying pathogenic mechanisms. We seek to uncover the molecular pathways that promote protein aggregation and the formation of amyloid deposits that cause neurodegeneration and cognitive impairments. Using a combination of biochemistry, genetics, and cell biology, we have identified several post-translational mechanisms including lysine acetylation, phosphorylation, and cysteine disulfide modifications that critically regulate many disease-associated proteins in the brain including the tau protein in AD and the TDP-43 protein present in ALS and FTLD patients. We have pioneered the concept that lysine acetylation, in particular, is an unanticipated, yet critical modification that promotes the evolution and maturation of pathological aggregates in a spectrum of neurodegenerative diseases. This raises the intriguing possibility of modification-targeted therapeutics to combat normal ageing mechanisms and a broad range of neurodegenerative diseases. Ultimately, by uncovering the mechanistic details that regulate normal and aberrant protein functions in the diseased brain, can we begin to uncover the molecular platform for future drug-based therapies against these debilitating diseases.
We utilize a multidisciplinary approach from the "bottom-up", starting at the protein level and progressing towards more relevant models to answer fundamental questions about protein function and aggregation in neurodegenerative disease.
Although clinically and pathologically distinct, the disorders shown below share a common underlying pathogenic mechanism in which normally soluble proteins become abnormally sequestered into protein aggregates that can exert toxic loss and gain of functions in a tissue-specific manner.
Current research projects:
1) Tau-mediated neurodegeneration in Alzheimer's disease
Above image: Tau acetylation causes increased tau aggregation in vitro and promotes the formation of tau tangles observed in AD brain (Cohen et al., Nat Commun, 2011).
Alzheimer’s disease (AD) is the leading cause of dementia worldwide. With an increase in ageing among the human population, we are currently faced with a looming AD epidemic unless we explore new therapeutic options that target the underlying basis of this disease. The signature brain lesions found in Alzheimer’s disease are plaques composed of the Ab protein and neurofibrillary tangles (NFTs) composed of the tau protein. In both cases, abnormal accumulation and clumping of these proteins occurs in AD brain leading to impaired neuron function and subsequent neurodegenerative symptoms including dementia. Therefore, if we can prevent the abnormal clumping, or aggregation, of these proteins using specific drugs, then we could potentially provide therapies to prevent neurodegeneration and the onset or progression of AD. To accomplish such a challenging feat, we require a careful understanding of the mechanisms that dictate protein aggregation in the diseased brain. Such information will provide the framework to understand the pathogenesis of Alzheimer’s disease.
One way to control protein function is via post-translational modifications (PTMs), which are chemical tags that allow proteins to navigate and communicate with their surrounding environment within a cell. One such modification referred to as acetylation can be chemically attached to a specific amino acid (i.e. lysine) present within the proteins in the brain. Importantly, acetylation can often result in abnormal alterations in protein functions, including the clumping similar to that observed in AD brain. Remarkably, we have recently discovered that acetylation of normal tau protein can transform tau into clumpy aggregates, also known as fibrils, that resemble the hallmark lesions observed in Alzheimer’s brain. Therefore, we speculate that abnormal acetylation in the brain can drive the formation tau clumps and subsequent neurodegenerative symptoms.
2) TDP-43 mediated neurodegeneration in ALS
TDP-43 modifications similarly promote aberrant pathology seen in diseased brain and spinal cord of ALS and FTLD-TDP patients. Understanding such post-translational mechanisms could lead to better therapeutic avenues to pursue for ALS, FTD and other diseases characterized by TDP-43 pathology.
3) Altered post-translationally modified proteome (PT-MAP) in neurodegenerative diseases.
Please contact me if you're interested in contributing to exciting research!
*****Open position for a postdoc fellow*****
We are recruiting a highly motivated postdoc to investigate pathogenesis of Alzheimer’s disease using mouse models. Brain techniques including sectioning, immunohistochemistry, tissue extraction, brain biochemistry, stereotactic mouse injections, and behavioral analysis will be performed on various transgenic and knockout mice. The candidate is expected to lead this project independently and manage several colonies of mice to address major questions regarding the tau protein in Alzheimer’s disease. Proficient record-keeping skills, presentation skills, and ability to collaborate with others in the lab is required. Must have experience handling mice, performing experiments on mouse tissue, and extracting mouse tissues for subsequent biochemical or immunohistological analysis. This posting can be accessed directly at https://unc.peopleadmin.com/postings/50730