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The Outer Brain: Ten Amazing Ways the Skin and Brain Connect - Five

How can the skin provide a way to detect brain abnormalities?

Much of my interest and research over the last decade has been on the connection between the skin and the brain, including searching for skin biomarkers to detect Alzheimer’s disease (AD) and the connection between Parkinson’s disease (PD) and melanoma.

Neurodegenerative diseases are characterized by the presence of abnormal aggregates of proteins in brain tissue. Among them, the presence of aggregates of phosphorylated Tau protein (p-Tau) is the hallmark of Alzheimer’s disease (AD) and other major neurodegenerative disorders such as corticobasal degeneration and frontotemporal dementia, and are implicated in Parkinson’s disease (PD) among others.

What is Tau? Traditionally, it was considered a cytoplasmic protein whose major biological function would be to stabilize microtubules and facilitate axonal transport. According to this view, in AD there is a hyperphosphorylation of Tau that leads to the intracellular accumulation of Tau in the form of neurofibrillary tangles. Now we know that Tau protects the nuclear and chromatin organization for proper gene expression throughout neuronal life. Tau protein transfer to the cytoplasm results in loss of the protector role of nuclear Tau and subsequent global chromatin disorganization. Therefore, the cytoplasmic Tau protein accumulations that characterize AD have been completely reinterpreted, as it is the search for new therapeutic solutions.

Let me briefly and simply explain the two key disease players and what we have found.  PD is a neurodegenerative disorder that triggers death of dopaminergic neurons within the brain’s substantia nigra. This disorder is characterized by intracellular inclusions primarily composed of proteinaceous α-synuclein amyloid fibrils.  Melanocytes are the pigmented cells that give rise to skin, hair and eye color, and melanoma is a potentially deadly cancer arising from melanocytes.  Interestingly, there is a significant coincidence of PD and melanoma that may suggest a shared pathophysiology.

Recently, we reported that PD and melanoma patients have increased staining for α-synuclein in their skin. We think that neurons and melanocytes, both derived from neuroectodermal cells, may share protein synthesis and regulation pathways that become dysfunctional in PD and melanoma. Therefore, uncovering the behavior of α-synuclein in melanoma could both provide novel approaches for treating melanoma and insights into the role of α-synuclein in PD.  As Dean and Lee (2021) noted, we should investigate how α-synuclein influences melanoma cell survival, because this may reveal new insights into α-synuclein function that may be used to prevent dopaminergic cell death and subsequently PD.

Identifying PD has been limited by inadequate sensitivity and specificity.  Various diagnostic tests have been utilized, including olfactory function testing, cardiovascular autonomic testing, biological fluids (including CSF and blood) testing and PET or SPECT imaging. According to Rodriguez-Leyva (2014, 2016) and Wang and collaborators (2021) skin deposition of misfolded α-synuclein is a potential biomarker for PD. For Donadio (2019)  “the autonomic skin innervation is a useful site for the search of abnormal α-syn aggregates since peripheral sympathetic nerves could be the earliest affected neural region and autonomic symptoms may precede the classical symptoms of synucleinopathy, such as motor dysfunction in PD.”

Although Tau protein has previously been assumed to be exclusive to the central nervous system, it is also found in peripheral tissues. My colleagues Maria E. Jimenez-Capdeville, Ildefonso Rodríguez-Leyva, William Eng and others, and I published our research in 2017 on whether there is a differential Tau expression in oral mucosa cells according to cognitive impairment.

Immunocytochemistry and immunofluorescence revealed the presence of Tau and four p-Tau forms in the cytoplasm and nucleus of oral mucosa cells. More positivity was present in subjects with cognitive impairment than in control subjects, both in the nucleus and cytoplasm, in a speckled pattern. The mRNA expression of Tau by quantitative real-time polymerase chain reaction was higher in SCI as compared with the control group.

Our findings demonstrated the higher presence of p-Tau and Tau transcript in the oral mucosa of cognitively-impaired subjects when compared with healthy subjects. The feasibility of p-Tau quantification by flow cytometry supported the prospective analysis of oral mucosa as a support tool for screening of proteinopathies in cognitively-impaired patients.  Utilizing oral swabs to gather our specimens and detecting biomarkers for dementia hopefully opens pathways for future researchers and patients themselves to assay these crucial markers and make key health decisions.

As a clinician and researcher, I truly enjoy working with my colleagues who have inquisitive minds and are searching to unlock the mysteries of human life.  Collaboration is a key to our progress and by sharing our important research and clinical findings, we can move ahead at a more effective and rapid pace.

Dementia, Parkinson’s Disease, skin cancer and many other issues that may be helped by robust skin biomarkers and research are among the most important public health issues of our time.  The sooner we can create new preventions and treatments based on the successful results of our collective hard work, the quicker we can alleviate the suffering of millions of diseased and debilitated co-inhabitants of our world.


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For more information, look at my YouTube series on the Brain-Skin Connections:

The Brain-Skin Connection Series - YouTube

Dr. Robert A. Norman

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