Bringing Structure to Biology
Disruption of the Mind
The consequences of neurodegenerative diseases are predicted to be one of the largest socioeconomic challenges of the near future. Understanding the molecular mechanisms underlying such diseases will be key to developing therapies. Our calendar image for July was inspired by the molecular structure one of the proteins implicated in Alzheimer’s disease.
Alzheimer's disease (AD), the leading cause of dementia worldwide, is a devastating condition. Yet, whilst epidemiology tells us the risk factors which correlate with the disease (e.g. age, depression, poor lifestyle, genetic makeup), a definitive cause has not yet been identified. AD shares many of the symptoms commonly found in other neurodegenerative conditions, including (but not limited to): poor short term memory, difficulty speaking, disorientation, mood and behavioural issues, and an ultimately fatal decline in bodily functions. The nature and progression of these symptoms can be particularly difficult for family and friends, and often necessitates substantial care arrangements. Typical symptoms, combined with cognitive tests and clinical observations, are usually required for a practical diagnosis of Alzheimer's disease, however an unambiguous verdict is only possible post-mortem after a detailed inspection of the brain.
Tangles of Tau
There are a number of well described hallmarks that define an AD brain, and most of the classical signs can be visually appreciated following microscopic analysis of specially treated samples. So called “negative” features correspond to the damage and loss of brain cells, whilst “positive” features correspond to different forms of aggregated proteins that cluster within and around neurons wherein they are thought to contribute to the disruption of normal brain function. Two principle forms of these clusters exist; the first (termed “plaques”) are dense objects made from fibrillar accumulations of the beta amyloid protein whereas the second (termed “tangles”) are filaments composed of the Tau protein. In a healthy brain, Tau acts to stabilise microtubules, but in AD ‘tangles’, it forms different structures considered to be aberrantly structured (misfolded). It is not known how these elements give rise to AD pathologies, although a tremendous global research effort is underway between academic teams and pharmaceutical companies exploring a wide range of scientific approaches.
A molecular understanding of these aberrant protein structures will be crucial to unpicking the disease and deriving effective treatments. There are currently many structures of fragments of Tau in the PDB, however most of these have been produced ex vivo. To understand the precise form of Tau tangles in vivo, Fitzpatrick et al made use of recent advances in cryoEM to visualise the structure of misfolded Tau directly from a post-mortem brain (see image below).
The cryo-EM structure of Tau filaments directly extracted from disease patients (PDB entry 5O3O). Individual tau proteins (distinct colours) share a common, self-templating, amyloid fold of eight β-strands, which serves to propagate the structure of the filament along its primary axis.
The complexity of AD undoubtedly increases the scale of the challenge required for improved understanding and effective treatment. However, these recent methodological advances, enabling researchers to visualise samples from patients’ brains could hopefully start to offer a deeper glimpse into the inner workings of the disease.
About the Artwork
July's calendar image was created using mixed media by Lucy Tunsley of the Stephen Perse Foundation Sixth Form College Cambridge, taking inspiration from PDB entry 5O3O. The representation of tau filaments related to Alzheimer's disease, highlights some of the personal and pathological chaos surrounding neurodegenerative conditions. Knotted, enmeshed objects represent characteristic plaques and neurofibrillary tangles; voids and channels reflect the absence of thought and memory.